Substituted indanone compounds as gpr119 modulators for the treatment of diabetes, obesity, dyslipidemia and related disorders

ABSTRACT

The present invention relates to indanone compounds. The indanone compounds are GPR119 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to the use of indanone compounds as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

The present invention relates to indanone compounds of the formula I

in which R1a, R1b, R1c, R2a, R2b, R2c, R3, R4, R11, R12, R30, R31, Y andZ are defined as indicated below. The indanone compounds I are GPR119modulators and useful for the prevention and/or treatment of diabetes,obesity, dyslipidemia and related disorders. The invention furthermorerelates to the use of indanone compounds of the formula I as activeingredients in pharmaceuticals, and pharmaceutical compositionscomprising them.

GPR119 is a G-protein coupled receptor which is expressed predominantlyin the beta cells of the pancreas and in the K- and L-cells of theintestine. In vitro studies have shown, that agonists of GPR119, viaactivation of the cAMP pathway in gut and pancreas derived cell lines,mediate the secretion of GLP-1 and insulin respectively. This supportsthe hypothesis, that modulators of GPR119, agonists in particular, mayhave utility to treat diabetes and related disorders by augmenting thesecretion of insulin and intestinal hormones like GIP, GLP-1 and PYY. Asthe secretion of insulin was found to be strictly glucose-dependent,induction of hypoglycemic episodes may largely be avoided. Furthermorebeneficial effects like reduced food intake may be expected from therelease of intestinal peptides. Stimulation of the beta cell byactivation of GPR119 may also improve beta cell function and beta cellmass. Studies of GPR119 agonists in rodents showed the predicted glucoselowering effects. For some such animal studies decreased food intake andweight loss was reported. Recently clinical trials with GPR119 agonistsadded evidence for a positive impact on lipid parameters i.e. elevationof HDL together with lowering of LDL and triglycerides in humans.WO2013/070463A2 discloses that GPR119 agonists may be used to treatabnormalities in blood lipids. In summary, modulators of GPR119,agonists in particular, may have therapeutic utility in the preventionand/or treatment of metabolic disorders in mammals and especially inhumans. Examples of such disorders and diseases include type 2 diabetesmellitus, type 1 diabetes mellitus, impaired glucose tolerance, insulinresistance, loss of beta cell function, hyperglycemia,hypercholesterolemia, dyslipidemia, hypertriglyceridemia, syndrome X,metabolic syndrome, obesity, fatty liver, steatosis, steatohepatitis,cirrhosis, micro- and marcovascular disorders, high blood pressure,chronic low grade inflammation, retinopathy, neuropathy, nephropathy,atherosclerosis, coronary heart disease, endothelial dysfunction andbone-related diseases such as osteoporosis, rheumatoid arthritis orosteoarthritis.

Several modulators of GPR119 are known. For example WO2011146335 andWO2012037393 describe piperidinyl-substituted lactams as GPR119modulators. WO2010048149 describes heterocyclic modulators of GPR119 forthe treatment of disease and their preparation. WO2004110994 describesthe preparation of piperazinyl-aryloxy andpiperazinyl-heteroaryloxy-N-aryl lactams as 5-HT1B ligands.

It was an aim of the invention to provide novel compounds as activeingredients in pharmaceuticals.

It was another aim of the invention to provide novel compounds whichwill lower blood glucose in mammals and which are suitable forprevention and/or treatment of diabetes, obesity, dyslipidemia andrelated disorders.

A further aim was to provide novel GPR119 modulators, especiallyagonists, which can be used therapeutically for the prevention and/ortreatment of diabetes, obesity, dyslipidemia and related disorders.

-   in which-   R30 is (CR11′R12′)_(n)-R32, NR17R18 or OR17;-   R31 is H or (CR11′R12′)_(m)-R32;-   n is 0, 1 or 2;-   m is 0, 1, 2 or 3;-   R11, R12 are independently of each other H or (C₁-C₆)-alkyl;    -   or R11 and R12 form together the group ═O;-   R11′, R12′ are independently of each other H or (C₁-C₆)-alkyl;-   R32 is (C₁-C₆)-alkyl, COOR13, CONR14R15, SO₂R16 or OH;-   R13 is H or (C₁-C₆)-alkyl;-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl,    (C₁-C₆)-alkyl substituted with OR17, or (C₃-C₆)-cycloalkyl;    -   or R14 and R15 form together with the N-atom on which they are        attached, a 4-, 5- or 6-membered heterocycle, optionally        containing an additional heteroatom selected from the list O, S        and NR18;        -   wherein the 4-, 5- or 6-membered heterocycle may be            optionally substituted with 1 to 3 groups selected from the            list (C₁-C₄)-alkyl and OR19;-   R16 is (C₁-C₆)-alkyl;-   R17 is H or (C₁-C₆)-alkyl;-   R18 is H or (C₁-C₆)-alkyl;-   R19 is H or (C₁-C₆)-alkyl;-   R1a, R1b, R1c are independently of each other H, F, Cl, Br,    (C₁-C₆)-alkyl or ON;-   R2a, R2b, R2c are independently of each other H, F, Cl, Br,    (C₁-C₆)-alkyl or ON;-   Y is N or CH;-   Z is a bond, O, CR5R5′, NR6, C═O, S, SO or SO₂;-   R5, R5′, R6 are independently of each other H or (C₁-C₄)-alkyl;-   R3 is a bond or (CR7R7′)_(p);-   p is 0, 1, 2, 3 or 4;-   R7, R7′ are independently of each other H or (C₁-C₆)-alkyl;-   R4 is (C₁-C₆)-alkyl, OR8, (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl,    4-, 5- or 6-membered heterocycle, phenyl or 5- or 6-membered    heteroaryl ring;    -   wherein the groups (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-,        5- or 6-membered heterocycle, phenyl, 5- or 6-membered        heteroaryl ring may be optionally substituted with 1 to 3 groups        selected from (C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl, hydroxy,        hydroxy-(C₁-C₄)-alkyl, (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl, oxo, F or        Cl;-   R8 is H, (C₁-C₆)-alkyl, hydroxy-(C₁-C₄)-alkyl or    (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl;    wherein at each occurrence the hydrogen atoms of alkyl groups may be    partially or fully replaced by fluorine atoms;    in any of its stereoisomeric forms, or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

In another group of embodiments

the 3-position of the central pyrrolidinone ring has (R)-configuration.

In another group of embodiments

R30 is (CR11′R12′)_(n)-R32.

In another group of embodiments

R31 is H.

In another group of embodiments

R11, R12 are H.

In another group of embodiments

R11′, R12′ are H.

In another group of embodiments

R32 is COOR13, CONR14R15, SO₂R16 or OH.

In another group of embodiments

R32 is COOR13, CONR14R15.

In another group of embodiments

R32 is CONR14R15.

In another group of embodiments

-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl or    (C₁-C₆)-alkyl substituted with OR17.

In another group of embodiments

R16 is CH₃.

In another group of embodiments

R1a, R1c are independently of each other H, F or CH₃.

In another group of embodiments

R1b is H.

In another group of embodiments

R1a is H or F.

In another group of embodiments

R1b and R1c are H.

In another group of embodiments

R2a is H, F or CH₃.

In another group of embodiments

R2b and R2c are H.

Y is N.

In another group of embodiments

Z is O.

In another group of embodiments

R7, R7′ are H.

In another group of embodiments

p is 0, 1 or 2.

In another group of embodiments

R4 is (C₁-C₆)-alkyl, OR8, (C₃-C₈)-cycloalkyl or phenyl;

-   -   wherein the groups (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl and phenyl        may be optionally substituted with 1 to 3 groups F;

In another group of embodiments

R4 is (C₃-C₆)-cycloalkyl, which is unsubstituted or substituted bymethyl.

In another group of embodiments

R3 is a bond.

In another group of embodiments

R3 is selected from the list CH₂ and CH₂—CH₂.

In another group of embodiments

R3 is CH₂.

In another group of embodiments the compound of the formula I is acompound of the formula Ia

in which

-   R30 is (CR11′R12′)_(n)-R32 or OR17;-   n is 0, 1 or 2;-   R11′, R12′ are independently of each other H or (C₁-C₆)-alkyl;-   R32 is COOR13, CONR14R15, SO₂R16 or OH;-   R13 is H or (C₁-C₆)-alkyl;-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl,    (C₁-C₆)-alkyl substituted with OR17, or (C₃-C₆)-cycloalkyl;    -   or R14 and R15 form together with the N-atom on which they are        attached, a 4-, 5- or 6-membered heterocycle, optionally        containing an additional heteroatom selected from the list O, S        and NR18;        -   wherein the 4-, 5- or 6-membered heterocycle may be            optionally substituted with 1 to 3 groups selected from the            list (C₁-C₄)-alkyl and OR19;-   R16 is (C₁-C₆)-alkyl;-   R17 is H or (C₁-C₆)-alkyl;-   R18 is H or (C₁-C₆)-alkyl;-   R19 is H or (C₁-C₆)-alkyl;-   R1a, R1c are independently of each other H, F, Cl, Br, (C₁-C₆)-alkyl    or ON;-   R2a is H, F, Cl, Br, (C₁-C₆)-alkyl or ON;-   R3 is a bond or (CR7R7′)_(p);-   p is 0, 1, 2, 3 or 4;-   R7, R7′ are independently of each other H or (C₁-C₆)-alkyl;-   R4 is (C₁-C₆)-alkyl, OR8, (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl,    4-, 5- or 6-membered heterocycle, phenyl or 5- or 6-membered    heteroaryl ring;    -   wherein the groups (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-,        5- or 6-membered heterocycle, phenyl, 5- or 6-membered        heteroaryl ring may be optionally substituted with 1 to 3 groups        selected from (C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl, hydroxy,        hydroxy-(C₁-C₄)-alkyl, (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl, oxo, F or        Cl;-   R8 is H, (C₁-C₆)-alkyl, hydroxy-(C₁-C₄)-alkyl or    (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl;    wherein at each occurrence the hydrogen atoms of alkyl groups may be    partially or fully replaced by fluorine atoms;    in any of its stereoisomeric forms, or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

In another group of embodiments the compound of the formula I is acompound of the formula Ia, in which

-   R30 is (CR11′R12′)_(n)-R32 or OR17;-   n is 0, 1 or 2;-   R11′, R12′ are independently of each other H or (C₁-C₆)-alkyl;-   R32 is COOR13, CONR14R15, SO₂R16 or OH;-   R13 is H or (C₁-C₆)-alkyl;-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl,    (C₁-C₆)-alkyl substituted with OR17, or (C₃-C₆)-cycloalkyl;    -   or R14 and R15 form together with the N-atom on which they are        attached, a 4-, 5- or 6-membered heterocycle, optionally        containing an additional heteroatom selected from the list O, S        and NR18;        -   wherein the 4-, 5- or 6-membered heterocycle may be            optionally substituted with 1 to 3 groups selected from the            list (C₁-C₄)-alkyl and OR19;-   R16 is (C₁-C₆)-alkyl;-   R17 is H or (C₁-C₆)-alkyl;-   R18 is H or (C₁-C₆)-alkyl;-   R19 is H or (C₁-C₆)-alkyl;-   R1a, R1c are independently of each other H, F, Cl, Br, (C₁-C₆)-alkyl    or ON;-   R2a is H, F, Cl, Br, (C₁-C₆)-alkyl or ON;-   R3 is bond, CH₂ or CH₂—CH₂;-   R4 is (C₁-C₆)-alkyl, OR8, (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl,    4-, 5- or 6-membered heterocycle, phenyl or 5- or 6-membered    heteroaryl ring;    -   wherein the groups (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-,        5- or 6-membered heterocycle, phenyl, 5- or 6-membered        heteroaryl ring may be optionally substituted with 1 to 3 groups        selected from (C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl, hydroxy,        hydroxy-(C₁-C₄)-alkyl, (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl, oxo, F or        CI;-   R8 is H, (C₁-C₆)-alkyl, hydroxy-(C₁-C₄)-alkyl or    (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl;    wherein at each occurrence the hydrogen atoms of alkyl groups may be    partially or fully replaced by fluorine atoms;    in any of its stereoisomeric forms, or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

In another group of embodiments the compound of the formula I is acompound of the formula Ia, in which

-   R30 is (CR11′R12′)_(n)-R32 or OR17;-   n is 0, 1 or 2;-   R11′, R12′ are independently of each other H or (C₁-C₆)-alkyl;-   R32 is COOR13, CONR14R15, SO₂R16 or OH;-   R13 is H or (C₁-C₆)-alkyl;-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl,    (C₁-C₆)-alkyl substituted with OR17, or (C₃-C₆)-cycloalkyl;    -   or R14 and R15 form together with the N-atom on which they are        attached, a 4-, 5- or 6-membered heterocycle, optionally        containing an additional heteroatom selected from the list O, S        and NR18;        -   wherein the 4-, 5- or 6-membered heterocycle may be            optionally substituted with 1 to 3 groups selected from the            list (C₁-C₄)-alkyl and OR19;-   R16 is (C₁-C₆)-alkyl;-   R17 is H or (C₁-C₆)-alkyl;-   R18 is H or (C₁-C₆)-alkyl;-   R19 is H or (C₁-C₆)-alkyl;-   R1a, R1c are independently of each other H, F, Cl, Br, (C₁-C₆)-alkyl    or CN;-   R2a is H, F, Cl, Br, (C₁-C₆)-alkyl or CN;-   R3 is bond, CH₂ or CH₂—CH₂;-   R4 (C₃-C₈)-cycloalkyl;    in any of its stereoisomeric forms, or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

In another group of embodiments the compound of the formula I is acompound of the formula Ia, in which

-   R30 is R32;-   R32 is CONR14R15, COOR13;-   R13 is H or (C₁-C₆)-alkyl;-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl or    (C₁-C₆)-alkyl substituted with OR17;    -   or R14 and R15 form together with the N-atom on which they are        attached, a 4-, 5- or 6-membered heterocycle, optionally        containing an additional heteroatom selected from the series O,        S and NR18;-   R17 is H or (C₁-C₆)-alkyl;-   R18 is H or (C₁-C₆)-alkyl;-   R1a, R1c are independently of each other H, F, Cl, Br, (C₁-C₆)-alkyl    or ON;-   R2a is H, F, Cl, Br, (C₁-C₆)-alkyl or ON;-   R3 is CH₂;-   R4 (C₃-C₆)-cycloalkyl;    in any of its stereoisomeric forms, or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

In another group of embodiments the compound of the formula I is acompound of the formula Ia, in which

-   R30 is R32;-   R32 is CONR14R15, COOR13;-   R14, R15 are independently of each other H, (C₁-C₆)-alkyl or    (C₁-C₆)-alkyl substituted with OR17;-   R17 is H or (C₁-C₆)-alkyl;-   R1a is H or F;-   R1c is H;-   R2a is H;-   R3 is CH₂;-   R4 (C₃-C₆)-cycloalkyl;    in any of its stereoisomeric forms, or a mixture of stereoisomeric    forms in any ratio, or a physiologically acceptable salt thereof.

In another embodiment compounds of the formula I are encompassedselected from the list Examples 1-01 to 1-18, 2-01 to 2-05 and 3-01 to3-11.

In another embodiment compounds of the formula I are encompassedselected from the following list:

-   (3R)-3-[[6-(4-Fluorophenoxy)-3-pyridyl]oxy]-1-[1-(2-hydroxyethyl)-3-oxo-indan-5-yl]pyrrolidin-2-one,-   methyl    2-[6-[3-(4-isopentyloxyphenoxy)-2-oxo-pyrrolidin-1-yl]-1-oxo-indan-2-yl]acetate,-   methyl    2-[5-[(3R)-3-[4-(4-fluorophenoxy)phenoxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetate,-   {6-[(R)-3-(6-cyclopropylmethoxy-pyridin-3-yloxy)-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl}-acetic    acid methyl ester,-   (3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-[7-fluoro-2-(2-hydroxyethyl)-3-oxo-indan-5-yl]pyrrolidin-2-one,-   methyl    2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetate,-   2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-2-(2-methoxy-2-oxo-ethyl)-1-oxo-indan-2-yl]acetic    acid,-   (3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-[1-(2-hydroxyethyl)-3-oxo-indan-5-yl]pyrrolidin-2-one,-   methyl    2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetate,-   methyl    6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-1-oxo-indane-2-carboxylate,-   methyl    2-[5-[(3R)-3-[[6-(cyclopropoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetate,-   methyl    2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-1-oxo-indan-2-yl]acetate,-   methyl    2-[5-[(3R)-3-[[6-(cyclopropoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetate,-   methyl    2-[(1S)-5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetate,-   methyl    2-[(1R)-5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetate,-   5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-N,N-dimethyl-3-oxo-indane-1-carboxamide,-   (3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-[7-fluoro-1-(hydroxymethyl)-3-oxo-indan-5-yl]pyrrolidin-2-one,-   (3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-[1-(hydroxymethyl)-3-oxo-indan-5-yl]pyrrolidin-2-one,-   {6-[(R)-3-(6-cyclopropylmethoxy-pyridin-3-yloxy)-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl}-acetic    acid,-   {5-[(R)-3-(6-Cyclopropylmethoxy-pyridin-3-yloxy)-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl}-acetic    acid,-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetic    acid,-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetic    acid,-   2-[(1S)-5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetic    acid,-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide,-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N-methyl-acetamide,-   N-cyclopropyl-2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetamide,-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]acetamide,-   2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl]acetamide,-   2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl]-N,N-dimethyl-acetamide,-   (3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-1-[7-fluoro-2-(2-morpholino-2-oxo-ethyl)-3-oxo-indan-5-yl]pyrrolidin-2-one,-   2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl]-N-methyl-acetamide,-   2-{6-[(R)-3-(6-cyclopropylmethoxy-pyridin-3-yloxy)-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl}-N-(2-hydroxy-ethyl)-acetamide,-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetamide    and-   2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide.

In another embodiment compounds of the formula I are encompassedselected from the following list:

-   5-[(3R)-3-[[6-(Cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-N,N-dimethyl-3-oxo-indane-1-carboxamide,-   2-[5-[(3R)-3-[[6-(cyclopropyl    methoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide,-   2-[5-[(3R)-3-[[6-(cyclopropyl    methoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N-methyl-acetamide,-   2-[6-[(3R)-3-[[6-(cyclopropyl    methoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl]-N,N-dimethyl-acetamide,-   2-[5-[(3R)-3-[[6-(cyclopropyl    methoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetamide    and-   2-[5-[(3R)-3-[[6-(cyclopropyl    methoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide.

In another embodiment the compound of the formula I is2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide.

In another embodiment the compound of the formula I is2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide.

Structural elements such as groups, substituents, hetero ring members,numbers or other features, for example alkyl groups, groups like R5,R5′, R7, R7′ etc., which can occur several times in the compounds of theformula I, can all independently of one another have at each occurrenceany of the indicated meanings and can in each case be identical to ordifferent from one another. For example, the alkyl groups in adialkylamino group can be identical or different.

Herein, the terms “including” and “comprising” are used in their open,non-limiting sense. As used herein, the terms “(C₁-C₆)” and so forthrefer to moieties having 1 to 6 carbon atoms and so forth, respectively.Within composed terms like “hydroxy-(C₀-C₄)-alkyl” the option“(C₀)-alkyl refers to a bond (i.e. in this case a directly bound hydroxygroup), or in case of an unsubstituted “(C₀)-alkyl” it refers to ahydrogen.

The term “alkyl”, as used herein, refers to saturated, monovalenthydrocarbon radicals. The term “alkenyl”, as used herein, refers tomonovalent hydrocarbon radicals, which contain at least onecarbon-carbon double bond, wherein each double bond can have E- orZ-configuration. The term “alkynyl”, as used herein, refers tomonovalent hydrocarbon radicals, which contain at least onecarbon-carbon triple bond. The alkyl, alkenyl and alkynyl groups can belinear, i.e. straight-chain, or branched. This also applies when theyare part of other groups, for example alkyloxy groups (=alkoxy groups,O-alkyl groups), alkyloxycarbonyl groups or alkyl-substituted aminogroups, or when they are substituted. Depending on the respectivedefinition, the number of carbon atoms in an alkyl group can be 1, 2, 3,4, 5 or 6, or 1, 2, 3, or 4. Examples of alkyl are methyl, ethyl, propylincluding n-propyl and isopropyl, butyl including n-butyl, sec-butyl,isobutyl and tert-butyl, pentyl including n-pentyl, 1-methylbutyl,isopentyl, neopentyl and tert-pentyl, hexyl including n-hexyl,3,3-dimethylbutyl and isohexyl. Double bonds and triple bonds in alkenylgroups and alkynyl groups respectively can be present in any positions.Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl(=allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl,hex-3-enyl, hex-4-enyl, prop-2-ynyl (=propargyl), but-2-ynyl,but-3-ynyl, hex-4-ynyl or hex-5-ynyl. Substituted alkyl groups, alkenylgroups and alkynyl groups can be substituted in any positions, providedthat the respective compound is sufficiently stable and is suitable forthe desired purpose such as use as a drug substance. The prerequisitethat a specific group and a compound of the formula I are sufficientlystable and suitable for the desired purpose such as use as a drugsubstance, applies in general with respect to the definitions of allgroups in the compounds of the formula I.

Independently of one another and independently of any othersubstituents, alkyl groups, divalent alkyl groups, alkenyl groups,alkynyl groups, cycloalkyl groups and heterocycloalkyl groups areoptionally substituted by one or more fluorine substituents which can belocated in any positions, i.e., the said groups can be unsubstituted byfluorine substituents or substituted by fluorine substituents, forexample by 1, 2 or 3, by 1 or 2, or by 1 fluorine substituents. Examplesof fluorine-substituted said groups are trifluoromethyl, difluoromethyland fluoromethyl.

The term “alkanediyl” or “alkylene”, as used herein, refers tosaturated, divalent hydrocarbon radicals. The term “alkenediyl”, as usedherein, refers to divalent hydrocarbon radicals, which contain at leastone carbon-carbon double bond, wherein each double bond can have E- orZ-configuration. The term “alkynediyl”, as used herein, refers todivalent hydrocarbon radicals, which contain at least one carbon-carbontriple bond. As far as applicable, the preceding explanations regardingalkyl, alkenyl and alkynyl groups apply correspondingly to alkanediyl,alkenediyl and alkynediyl groups, which thus can likewise be linear andbranched. Examples of divalent alkyl groups are —CH₂— (=methylene),—CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂— and —CH₂—C(CH₃)₂—.

The term “cycloalkyl”, as used herein, unless otherwise indicated,refers to a monovalent radical of a saturated hydrocarbon ring system,which is monocyclic. In a monocyclic cycloalkyl group the number of ringcarbon atoms can be for example 3, 4, 5, 6, 7 or 8. In one embodiment ofthe invention, the number of ring carbon atoms in a cycloalkyl group,independently of the number of ring carbon atoms in any other cycloalkylgroup is 3, 4, 5 or 6, in another embodiment 3 or 4, in anotherembodiment 3, in another embodiment 5 or 6, in another embodiment 5, inanother embodiment 6. Examples of cycloalkyl groups are cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. The term “heterocycle”, as usedherein, unless otherwise indicated, refers to a cycloalkyl as definedabove, in which 1, 2, 3 or 4 carbon atoms are replaced by nitrogen oroxygen atoms, provided that the heterocycloalkyl system is stable andsuitable as a subgroup for the desired purpose of the compound of theformula I such as use as a drug substance. Depending on the definitionof the respective heterocyclic group, in one embodiment of the inventionthe number of ring heteroatoms which can be present in a heterocyclicgroup, independently of the number of ring heteroatoms in any otherheterocyclic group, is 1 or 2, in another embodiment 2, in anotherembodiment 1, wherein the ring heteroatoms can be identical ordifferent. The heterocycloalkyl group can be attached by any ring carbonatom or saturated ring nitrogen atom, with the exception of spiro- orbridgehead atoms.

Exemplary monocyclic heterocycloalkyl groups are derived from, but notlimited to, the ring systems azetidine, oxetane, pyrrolidine,tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine,tetrahydropyran or 1,4-dioxane:

In one embodiment monocyclic heterocycloalkyl groups are derived fromazetidine, pyrrolidine, piperidine, piperazine or morpholine:

The term “aryl”, as used herein, refers to a radical derived from anaromatic hydrocarbon by removal of one hydrogen, such as phenyl.

The term “heteroaryl” as used herein, refers to a radical derived from afully unsaturated monocyclic ring system, in which 1, 2 or 3 carbonatoms are replaced by heteroatoms. The ring heteroatoms are generallychosen from N, O and S, wherein N includes ring nitrogen atoms whichcarry a hydrogen atom or a substituent as well as ring nitrogen atomswhich do not carry a hydrogen atom or a substituent. Ring heteroatomscan be located in any position, provided that the heterocyclic system isstable and suitable as a subgroup for the desired purpose of thecompound of the formula I such as use as a drug substance. Heteroarylradicals are derived from 5-membered or 6-membered monocyclic rings.

Exemplary heteroaryl systems are derived from, but not limited to, thefollowing ring systems: pyrrole, furan, thiophene, imidazole, pyrazole,oxazole (=[1,3]oxazole), isoxazole (=[1,2]oxazole), thiazole(=[1,3]thiazole), isothiazole (=[1,2]thiazole), [1,2,3]triazole,[1,2,4]triazole, [1,2,4]oxadiazole, [1,3,4]oxadiazole,[1,2,4]thiadiazole, [1,3,4]thiadiazole, pyridine, pyridazine,pyrimidine, pyrazine, [1,2,3]triazine, [1,2,4]triazine or[1,3,5]triazine:

Groups like phenyl and residues of aromatic heterocycles which areoptionally substituted by one or more substituents, can be unsubstitutedor substituted, for example by 1, 2 or 3, or by 1 or 2, or by 1,identical or different substituents which can be located in anypositions. Aromatic nitrogen heterocycles which in the parent ringsystem carry a hydrogen atom on a ring nitrogen atom in a 5-memberedring, such as a pyrrole or imidazole ring, for example, can besubstituted on ring carbon atoms and/or on such ring nitrogen atoms. Inone embodiment of the invention, substituents on such ring nitrogenatoms are chosen from (C₁-C₄)-alkyl groups, i.e. such ring nitrogenatoms in aromatic heterocycles carry a hydrogen atom or a (C₁-C₄)-alkylsubstituent. When it is stated with respect to ring nitrogen atoms inaromatic heterocycles and any other heterocycles that they can carry ahydrogen atom or a substituent, such ring nitrogen atoms either carry ahydrogen atom or a substituent or they do not carry a hydrogen atom orsubstituent. Ring nitrogen atoms which carry a hydrogen atom or asubstituent, occur in a nitrogen-containing aromatic 5-membered ring asis present in pyrrole or imidazole for example, and in a non-aromaticring including a saturated ring. Ring nitrogen atoms which do not carrya hydrogen atom or a substituent unless they are present in positivelycharged form, including any further ring nitrogen atoms in addition toring nitrogen atoms which carry a hydrogen atom or a substituent, occurin an aromatic ring as is present in thiazole, imidazole or pyridine,for example, and in a non-aromatic ring in which they are part of adouble bond, and they occur as ring nitrogen atoms via which a ring isbonded. Suitable ring nitrogen atoms in aromatic heterocycles in thecompounds of the formula I, such as the ring nitrogen atom in a pyridinering, can in general also be present as N-oxide or as quaternary salt,for example as N—(C₁-C₄)-alkyl salt such as N-methyl salt, wherein inone embodiment of the invention the counter anion in such quaternarysalt is a physiologically acceptable anion which is derived from an acidthat forms a physiologically acceptable salt.

In monosubstituted phenyl groups, the substituent can be located in the2-position, the 3-position or the 4-position. In disubstituted phenylgroups, the substituents can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. Intrisubstituted phenyl groups, the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position or 3,4,5-position.

Ring heteroatoms can be located in any positions, provided that theheterocyclic system is known in the art and is stable and suitable as asubgroup for the desired purpose of the compound of the formula I suchas use as a drug substance. In one embodiment of the invention, two ringoxygen atoms cannot be present in adjacent ring positions of anyheterocycle, in another embodiment two ring heteroatoms chosen fromoxygen and sulfur cannot be present in adjacent ring positions of anyheterocycle. Substituents on heterocyclic groups can be located in anypositions. For example, in a pyridin-2-yl group substituents can belocated in the 3-position and/or 4-position and/or 5-position and/or6-position, in a pyridin-3-yl group substituent can be located in the2-position and/or 4-position and/or 5-position and/or 6-position, in apyridin-4-yl group substituents can be located in the 2-position and/or3-position and/or 5-position and/or 6-position.

When an oxo group is bonded to a carbon atom, it replaces two hydrogenatoms on a carbon atom of the parent system. Thus, if a CH₂ group in achain or a ring is substituted by oxo, i.e. by a doubly bonded oxygenatom, it becomes a CO group. Evidently, an oxo group cannot occur as asubstituent on a carbon atom in an aromatic ring such as in a phenylgroup, for example.

The present invention includes all stereoisomeric forms of the compoundsof the formula I and their salts and solvates. With respect to eachchiral center, independently of any other chiral center, the compoundsof the formula I can be present in S configuration or substantially Sconfiguration, or in R configuration or substantially R configuration,or as a mixture of the S isomer and the R isomer in any ratio. Theinvention includes all possible enantiomers and diastereomers andmixtures of two or more stereoisomers, for example mixtures ofenantiomers and/or diastereomers, in all ratios. Thus, compoundsaccording to the invention which can exist as enantiomers can be presentin enantiomerically pure form, both as levorotatory and asdextrorotatory antipodes, and in the form of mixtures of the twoenantiomers in all ratios including racemates. In the case of a E/Zisomerism, or cis/trans isomerism, for example on double bonds or ringssuch as cycloalkyl rings, the invention includes both the E form and Zform, or the cis form and the trans form, as well as mixtures of theseforms in all ratios. In one embodiment of the invention, a compoundwhich can occur in two or more stereoisomeric forms is a pure, orsubstantially pure, individual stereoisomer. The preparation ofindividual stereoisomers can be carried out, for example, by separationof a mixture of isomers by customary methods, for example bychromatography or crystallization, by the use of stereochemicallyuniform starting materials in the synthesis, or by stereoselectivesynthesis. Optionally, a derivatization can be carried out before aseparation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at the stage of the compound of theformula I or at the stage of a starting material or an intermediateduring the synthesis. The present invention also includes all tautomericforms of the compounds of the formula I and their salts and solvates.

In case the compounds of the formula I contain one or more acidic and/orbasic groups, i.e. salt-forming groups, the invention also includestheir corresponding physiologically or toxicologically acceptable salts,i.e. non-toxic salts, in particular their pharmaceutically acceptablesalts.

The present invention furthermore includes all solvates of compounds ofthe formula I, for example hydrates or adducts with alcohols such as(C₁-C₄)-alkanols, active metabolites of the compounds of the formula I,and also prodrugs and derivatives of the compounds of the formula Iwhich in vitro may not necessarily exhibit pharmacological activity butwhich in vivo are converted into pharmacologically active compounds, forexample esters or amides of carboxylic acid groups.

The compounds of the present invention can be widely combined with otherpharmacologically active compounds, such as all drugs mentioned in theRote Liste 2014, e.g. all antidiabetics mentioned in the Rote Liste2014, chapter 12, all weight-reducing agents or appetite suppressantsmentioned in the Rote Liste 2014, chapter 06, all lipid-lowering agentsmentioned in the Rote Liste 2014, chapter 58, all antihypertensivesmentioned in the Rote Liste 2014 chapter 17, all nephroprotectivesmentioned in the Rote Liste, or all diuretics mentioned in the RoteListe 2014, chapter 36.

The active ingredient combinations can be applied either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation. When administered separately,administration may occur simultaneously or sequentially, in any order.The amount of the compound of the invention and the otherpharmaceutically active ingredient(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. The administration of the combination may beconcomitantly in: (1) a unitary pharmaceutical composition including allpharmaceutically active ingredients; or (2) separate pharmaceuticalcompositions each including at least one of the pharmaceutically activeingredients. Alternatively, the combination may be administeredseparately in a sequential manner wherein one treatment agent isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

Most of the active ingredients mentioned hereinafter are disclosed inthe USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2014.

Therapeutic agents which are suitable for combinations include, forexample, antidiabetic agents such as:

Insulin and insulin derivatives, for example: insulin glargine (e.g.Lantus®), higher than 100 U/mL concentrated insulin glargine, e.g.270-330 U/mL of insulin glargine or 300 U/mL of insulin glargine (asdisclosed in EP 2387989), insulin glulisine (e.g. Apidra®), insulindetemir (e.g. Levemir®), insulin lispro (e.g. Humalog®, Liprolog®),insulin degludec (e.g. DegludecPlus®, IdegLira (NN9068)), insulin aspartand aspart formulations (e.g. NovoLog®), basal insulin and analogues(e.g. LY2605541, LY2963016, NN1436), PEGylated insulin lispro (e.g.LY-275585), long-acting insulins (e.g. NN1436, Insumera (PE0139),AB-101, AB-102, Sensulin LLC), intermediate-acting insulins (e.g.Humulin®N, Novolin®N), fast-acting and short-acting insulins (e.g.Humulin® R, Novolin® R, Linjeta® (VIAject®), PH20 insulin, NN1218,HinsBet®), premixed insulins, SuliXen®, NN1045, insulin plus Symlin®,PE-0139, ACP-002 hydrogel insulin, and oral, inhalable, transdermal andbuccal or sublingual insulins (e.g. Exubera®, Nasulin®, Afrezza®,insulin tregopil, TPM-02 insulin, Capsulin®, Oral-Iyn®, Cobalamin® oralinsulin, ORMD-0801, Oshadi oral insulin, NN1953, NN1954, NN1956,VIAtab®). Also suitable are those insulin derivatives which are bondedto albumin or another protein by a bifunctional linker.

Glucagon-like-peptide 1 (GLP-1), GLP-1 analogues, and GLP-1 receptoragonists, for example: lixisenatide (e.g. Lyxumia®), exenatide (e.g.exendin-4, rExendin-4, Byetta®, Bydureon®, exenatide NexP), liraglutide(e.g. Victoza®), semaglutide, taspoglutide, albiglutide, dulaglutide,ACP-003, CJC-1134-PC, GSK-2374697, PB-1023, TTP-054, langlenatide(HM-11260C), CM-3, GLP-1 Eligen, AB-201, ORMD-0901, NN9924, NN9926,NN9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, ZP-3022,CAM-2036, DA-3091, DA-15864, ARI-2651, ARI-2255, exenatide-XTEN(VRS-859), exenatide-XTEN+Glucagon-XTEN (VRS-859+AMX-808) andpolymer-bound GLP-1 and GLP-1 analogues.

Dual GLP-1/GIP agonists (e.g. RG-7697 (MAR-701), MAR-709, BHM081,BHM089, BHM098).

Dual GLP-1/glucagon receptor agonists (e.g. BHM-034, OAP-189(PF-05212389, TKS-1225), TT-401/402, ZP2929, LAPS-HMOXM25, MOD-6030).

Dual GLP-1/gastrin agonists (e.g. ZP-3022).

Other suitable combination partners are:

Further gastrointestinal peptides such as peptide YY 3-36 (PYY3-36) oranalogues thereof and pancreatic polypeptide (PP) or analogues thereof.

Glucagon receptor agonists or antagonists, glucose-dependentinsulinotropic polypeptide (GIP) receptor agonists or antagonists,ghrelin antagonists or inverse agonists, xenin and analogues thereof.

Dipeptidyl peptidase-IV (DPP-4) inhibitors, for example: alogliptin(e.g. Nesina®, Kazano®), linagliptin (e.g. Ondero®, Trajenta®,Tradjenta®, Trayenta®), saxagliptin (e.g. Onglyza® Komboglyze XR®),sitagliptin (e.g. Januvia®, Xelevia®, Tesavel®, Janumet®, Velmetia®,Juvisync®, Janumet XR®), anagliptin, teneligliptin (e.g. Tenelia®),trelagliptin, vildagliptin (e.g. Galvus®, Galvumet®), gemigliptin,omarigliptin, evogliptin, dutogliptin, DA-1229, MK-3102, KM-223,KRP-104, PBL-1427, Pinoxacin hydrochloride, and Ari-2243.

Sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, for example:canagliflozin, dapagliflozin, remogliflozin, remogliflozin etabonate,sergliflozin, empagliflozin, ipragliflozin, tofogliflozin,luseogliflozin, ertugliflozin, EGT-0001442, LIK-066, SBM-TFC-039, andKGA-3235 (DSP-3235).

Dual inhibitors of SGLT-2 and SGLT-1 (e.g. LX-4211, LIK066).

SGLT-1 inhibitors (e.g. LX-2761, KGA-3235) or SGLT-1 inhibitors incombination with anti-obesity drugs such as ileal bile acid transfer(IBAT) inhibitors (e.g. GSK-1614235+GSK-2330672).

Biguanides (e.g. metformin, buformin, phenformin).

Thiazolidinediones (e.g. pioglitazone, rosiglitazone), glitazoneanalogues (e.g. lobeglitazone).

Peroxisome proliferator-activated receptors (PPAR-)(alpha, gamma oralpha/gamma) agonists or modulators (e.g. saroglitazar (e.g. Lipaglyn®),GFT-505), or PPAR gamma partial agonists (e.g. Int-131).

Sulfonylureas (e.g. tolbutamide, glibenclamide, glimepiride, Amaryl®,glipizide) and meglitinides (e.g. nateglinide, repaglinide,mitiglinide).

Alpha-glucosidase inhibitors (e.g. acarbose, miglitol, voglibose).

Amylin and amylin analogues (e.g. pramlintide, Symlin®).

G-protein coupled receptor 119 (GPR119) agonists (e.g. GSK-1292263,PSN-821, MBX-2982, APD-597, ARRY-981, ZYG-19, DS-8500, HM-47000,YH-Chem1).

GPR40 agonists (e.g. TUG-424, P-1736, P-11187, JTT-851, GW9508,CNX-011-67, AM-1638, AM-5262).

GPR120 agonists and GPR142 agonists.

Systemic or low-absorbable TGR5 (GPBAR1=G-protein-coupled bile acidreceptor 1) agonists (e.g. INT-777, XL-475, SB756050).

Other suitable combination partners are:

Diabetes immunotherapeutics, for example: oral C—C chemokine receptortype 2 (CCR-2) antagonists (e.g. CCX-140, JNJ-41443532), interleukin 1beta (IL-1β) antagonists (e.g. AC-201), or oral monoclonal antibodies(MoA) (e.g. methalozamide, VVP808, PAZ-320, P-1736, PF-05175157,PF-04937319).

Anti-inflammatory agents for the treatment of the metabolic syndrome anddiabetes, for example: nuclear factor kappa B inhibitors (e.g.Triolex®).

Adenosine monophosphate-activated protein kinase (AMPK) stimulants, forexample: Imeglimin (PXL-008), Debio-0930 (MT-63-78), R-118.

Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 (11-beta-HSD-1)(e.g. LY2523199, BMS770767, RG-4929, BMS816336, AZD-8329, HSD-016,BI-135585).

Activators of glucokinase (e.g. PF-04991532, TTP-399 (GK1-399), GKM-001(ADV-1002401), ARRY-403 (AMG-151), TAK-329, TMG-123, ZYGK1).

Inhibitors of diacylglycerol O-acyltransferase (DGAT) (e.g. pradigastat(LCQ-908)), inhibitors of protein tyrosine phosphatase 1 (e.g.trodusquemine), inhibitors of glucose-6-phosphatase, inhibitors offructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase,inhibitors of phosphoenol pyruvate carboxykinase, inhibitors of glycogensynthase kinase, inhibitors of pyruvate dehydrogenase kinase.

Modulators of glucose transporter-4, somatostatin receptor 3 agonists(e.g. MK-4256).

One or more lipid lowering agents are also suitable as combinationpartners, for example: 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase(HMG-CoA-reductase) inhibitors such as simvastatin (e.g. Zocor®, Inegy®,Simcor®), atorvastatin (e.g. Sortis®, Caduet®), rosuvastatin (e.g.Crestor®), pravastatin (e.g. Lipostat®, Selipran®), fluvastatin (e.g.Lescol®), pitavastatin (e.g. Livazo®, Livalo®), lovastatin (e.g.Mevacor®, Advicor®), mevastatin (e.g. Compactin®), rivastatin,cerivastatin (Lipobay®), fibrates such as bezafibrate (e.g. Cedur®retard), ciprofibrate (e.g. Hyperlipen®), fenofibrate (e.g. Antara®,Lipofen®, Lipanthyl®), gemfibrozil (e.g. Lopid®, Gevilon®), etofibrate,simfibrate, ronifibrate, clinofibrate, clofibride, nicotinic acid andderivatives thereof (e.g. niacin, including slow release formulations ofniacin), nicotinic acid receptor 1 agonists (e.g. GSK-256073),PPAR-delta agonists, acetyl-CoA-acetyltransferase (ACAT) inhibitors(e.g. avasimibe), cholesterol absorption inhibitors (e.g. ezetimibe,Ezetrol®, Zetia®, Liptruzet®, Vytorin®, S-556971), bile acid-bindingsubstances (e.g. cholestyramine, colesevelam), ileal bile acid transport(IBAT) inhibitors (e.g. GSK-2330672, LUM-002), microsomal triglyceridetransfer protein (MTP) inhibitors (e.g. Iomitapide (AEGR-733), SLx-4090,granotapide), modulators of proprotein convertase subtilisin/kexin type9 (PCSK9) (e.g. alirocumab (REGN727/SAR236553), AMG-145, LGT-209,PF-04950615, MPSK3169A, LY3015014, ALD-306, ALN-PCS, BMS-962476,SPC5001, ISIS-394814, 1620, LGT-210, 1D05, BMS-PCSK9Rx-2, SX-PCK9,RG7652), LDL receptor up-regulators, for example liver selective thyroidhormone receptor beta agonists (e.g. eprotirome (KB-2115), MB07811,sobetirome (QRX-431), VIA-3196, ZYT1), HDL-raising compounds such as:cholesteryl ester transfer protein (CETP) inhibitors (e.g. anacetrapib(MK0859), dalcetrapib, evacetrapib, JTT-302, DRL-17822, TA-8995, R-1658,LY-2484595, DS-1442), or dual CETP/PCSK9 inhibitors (e.g. K-312),ATP-binding cassette (ABC1) regulators, lipid metabolism modulators(e.g. BMS-823778, TAP-301, DRL-21994, DRL-21995), phospholipase A2(PLA2) inhibitors (e.g. darapladib, Tyrisa®, varespladib, rilapladib),ApoA-I enhancers (e.g. RVX-208, CER-001, MDCO-216, CSL-112), cholesterolsynthesis inhibitors (e.g. ETC-1002), lipid metabolism modulators (e.g.BMS-823778, TAP-301, DRL-21994, DRL-21995) and omega-3 fatty acids andderivatives thereof (e.g. icosapent ethyl (AMR101), Epanova®, AKR-063,NKPL-66, PRC-4016, CAT-2003).

Other suitable combination partners are one or more active substancesfor the treatment of obesity, such as for example:

Bromocriptine (e.g. Cycloset®, Parlodel®), phentermine and phentermineformulations or combinations (e.g. Adipex-P, Ionamin, Qsymia®),benzphetamine (e.g. Didrex®), diethylpropion (e.g. Tenuate®),phendimetrazin (e.g. Adipost®, Bontril®), bupropion and combinations(e.g. Zyban®, Wellbutrin XL®, Contrave®, Empatic®), sibutramine (e.g.Reductil®, Meridia®), topiramat (e.g. Topamax®), zonisamid (e.g.Zonegran®), tesofensine, opioid antagonists such as naltrexone (e.g.Naltrexin®, naltrexone+bupropion), cannabinoid receptor 1 (CB1)antagonists (e.g. TM-38837), melanin-concentrating hormone (MCH-1)antagonists (e.g. BMS-830216, ALB-127158(a)), MC4 receptor agonists andpartial agonists (e.g. AZD-2820, RM-493), neuropeptide Y5 (NPY5) or NPY2antagonists (e.g. velneperit, S-234462), NPY4 agonists (e.g. PP-1420),beta-3-adrenergic receptor agonists, leptin or leptin mimetics, agonistsof the 5-hydroxytryptamine 2c (5HT2c) receptor (e.g. Iorcaserin,Belviq®), pramlintide/metreleptin, lipase inhibitors such as cetilistat(e.g. Cametor®), orlistat (e.g. Xenical®, Calobalin®), angiogenesisinhibitors (e.g. ALS-L1023), betahistidin and histamine H3 antagonists(e.g. HPP-404), AgRP (agouti related protein) inhibitors (e.g. TTP-435),serotonin re-uptake inhibitors such as fluoxetine (e.g. Fluctine®),duloxetine (e.g. Cymbalta®), dual or triple monoamine uptake inhibitors(dopamine, norepinephrine and serotonin re-uptake) such as sertraline(e.g. Zoloft®), tesofensine, methionine aminopeptidase 2 (MetAP2)inhibitors (e.g. beloranib), and antisense oligonucleotides againstproduction of fibroblast growth factor receptor 4 (FGFR4) (e.g.ISIS-FGFR4Rx) or prohibitin targeting peptide-1 (e.g. Adipotide®).

Moreover, combinations with drugs for influencing high blood pressure,chronic heart failure or atherosclerosis, for example: nitric oxidedonors, AT1 antagonists or angiotensin II (AT2) receptor antagonistssuch as telmisartan (e.g. Kinzal®, Micardis®), candesartan (e.g.Atacand®, Blopress®), valsartan (e.g. Diovan®, Co-Diovan®), losartan(e.g. Cosaar®), eprosartan (e.g. Teveten®), irbesartan (e.g. Aprovel®,CoAprovel®), olmesartan (e.g. Votum®, Olmetec®), tasosartan, azilsartan(e.g. Edarbi®), dual angiotensin receptor blockers (dual ARBs),angiotensin converting enzyme (ACE) inhibitors, ACE-2 activators, renininhibitors, prorenin inhibitors, endothelin converting enzyme (ECE)inhibitors, endothelin receptor (ET1/ETA) blockers, endothelinantagonists, diuretics, aldosterone antagonists, aldosterone synthaseinhibitors, alpha-blockers, antagonists of the alpha-2 adrenergicreceptor, beta-blockers, mixed alpha-/beta-blockers, calciumantagonists, calcium channel blockers (CCBs), nasal formulations of thecalcium channel blocker diltiazem (e.g. CP-404), dualmineralocorticoid/CCBs, centrally acting antihypertensives, inhibitorsof neutral endopeptidase, aminopeptidase-A inhibitors, vasopeptideinhibitors, dual vasopeptide inhibitors such as neprilysin-ACEinhibitors or neprilysin-ECE inhibitors, dual-acting ATreceptor-neprilysin inhibitors, dual AT1/ETA antagonists, advancedglycation end-product (AGE) breakers, recombinant renalase, bloodpressure vaccines such as anti-RAAS(renin-angiotensin-aldosteron-system) vaccines, AT1- or AT2-vaccines,drugs based on hypertension pharmacogenomics such as modulators ofgenetic polymorphisms with antihypertensive response, thrombocyteaggregation inhibitors, and others or combinations thereof are suitable.

In another aspect, this invention relates to the use of a compoundaccording to the invention or a physiologically acceptable salt thereofcombined with at least one of the active substances described above as acombination partner, for preparing a medicament which is suitable forthe treatment or prevention of diseases or conditions which can beaffected by binding to the GPR119 and modulating its activity. This ispreferably a disease in the context of the metabolic syndrome,particularly one of the diseases or conditions listed above, mostparticularly diabetes or obesity or complications thereof.

The use of the compounds according to the invention, or aphysiologically acceptable salt thereof, in combination with one or moreactive substances may take place simultaneously, separately orsequentially.

The use of the compound according to the invention, or a physiologicallyacceptable salt thereof, in combination with another active substancemay take place simultaneously or at staggered times, but particularlywithin a short space of time. If they are administered simultaneously,the two active substances are given to the patient together; if they areused at staggered times, the two active substances are given to thepatient within a period of less than or equal to 12 hours, butparticularly less than or equal to 6 hours.

Consequently, in another aspect, this invention relates to a medicamentwhich comprises compounds according to the invention or aphysiologically acceptable salt of such a compound and at least one ofthe active substances described above as combination partners,optionally together with one or more inert carriers and/or diluents.

The compounds according to the invention, or physiologically acceptablesalt or solvate thereof, and the additional active substance to becombined therewith may both be present together in one formulation, forexample a tablet or capsule, or separately in two identical or differentformulations, for example as so-called kit-of-parts.

Compounds according to the invention can be administered to animals, inparticular to mammals including humans, as pharmaceuticals bythemselves, in mixtures with one another, or in the form ofpharmaceutical compositions. The administration can be carried outorally, for example in the form of tablets, film-coated tablets,sugar-coated tablets, granules, hard and soft gelatin capsules,solutions including aqueous, alcoholic and oily solutions, juices,drops, syrups, emulsions or suspensions, rectally, for example in theform of suppositories, or parenterally, for example in the form ofsolutions for subcutaneous, intramuscular or intravenous injection orinfusion, in particular aqueous solutions.

Suitable pharmaceutical compositions for oral administration may be inthe form of separate units, for example capsules, cachets, lozenges ortablets, each of which contains a defined amount of the compound offormula I; as powders or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional ingredients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surfactant(s)/dispersant(s) in a suitable machine. Molded tabletscan be produced by molding the compound, which is in powder form and hasbeen moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise lozenges which contain a compound of formula Iwith a flavoring, typically sucrose, and gum arabic or tragacanth, andpastilles which comprise the compound in an inert base such as gelatinand glycerol or sucrose and gum arabic.

Coated formulations and coated slow-release formulations, especiallyacid- and gastric juice-resistant formulations, also belong within theframework of the invention. Suitable coatings resistant to gastric juicecomprise cellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula I with one or more conventionalsolid carriers, for example cocoa butter, and shaping the resultingmixture.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain 0.1 to 5% by weight ofthe active compound.

Other suitable administration forms are, for example, percutaneous ortopical administration, for example in the form of ointments, creams,tinctures, sprays, powders or transdermal therapeutic systems, orinhalative administration, for example in the form of nasal sprays oraerosol mixtures, or forms such as microcapsules, implants or rods.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. The carriers used may be petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of 0.1 to15% by weight of the composition, for example 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses may be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular option is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Compounds according to the invention can additionally be used in systemsfor local drug delivery, for example in coated stents for preventing orreducing in-stent restenosis or by applying them locally by means of acatheter. The appropriate administration form depends, among others, onthe disease to be treated and on its severity.

The dosing of compounds according to the invention to achieve thedesirable therapeutic effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, 0.1 ng to 100 mg, typically1 ng to 100 mg, per milliliter. Single doses may contain, for example, 1mg to 10 g of the active ingredient. Thus, ampoules for injections maycontain, for example, from 1 mg to 100 mg, and orally administrablesingle-dose formulations, for example tablets or capsules, may contain,for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. Forprevention and/or treatment of the abovementioned conditions, thecompounds of the formula I themselves may be used as the compound, butthey are preferably present with a compatible carrier in the form of apharmaceutical composition. The carrier must, of course, be acceptablein the sense that it is compatible with the other ingredients of thecomposition and is not harmful for the patient's health. The carrier maybe a solid or a liquid or both and is preferably formulated with thecompound as a single dose, for example as a tablet, which may contain0.05% to 95% by weight of the active ingredient. Other pharmaceuticallyactive substances may likewise be present, including other compounds offormula I. The pharmaceutical compositions of the invention can beproduced by one of the known pharmaceutical methods, which essentiallyconsist of mixing the ingredients with pharmacologically acceptablecarriers and/or excipients.

Another subject of the present invention are processes for thepreparation of the compounds of the formula I and their salts andsolvates, by which the compounds are obtainable and which are outlinedin the following.

ABBREVIATIONS

Abbreviations within this document have their common meanings unlessdefined otherwise herein. An exemplary list of abbreviations used, canbe found below.

Abbreviation Meaning Ac acetyl amu atomic mass unit atm atmosphere(pressure unit, 101325 Pa) BSA bovine serum albumin cAMP cyclicadenosine monophosphate cat. catalyst/catalyzed CDI carbonyl diimidazoledba dibenzylideneacetone DCM dichloromethane DEAD diethylazodicarboxylate DIAD diisopropyl azodicarboxylate DIPEAdiisopropyl-ethyl-amine DMEM Dulbecco's modified eagle medium DMFdimethylformamide DMSO dimethylsulfoxide dppf diphenylphosphinoferroceneEA ethyl acetate EC₅₀ concentration causing 50% of the maximal responseEDCI ethyl dimethylaminopropyl carbodiimide ESI electrospray ionizationFA formic acid FCS fetal calf serum GPR119 G-protein coupled receptor119 h hour(s) Hal halogen (atom) HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uroniumhexafluorophosphate HBSS Hank's buffered salt solution HEK 293 humanembryonic kidney 293 HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonicacid HOBt 1-hydroxy-benzotriazole HPLC high pressure liquidchromatography HTRF homogenous time-resolved fluorescence IBMX1-methyl-3-(2-methylpropyl)-7H-purine-2,6-dione LCMS liquidchromatography coupled mass spectroscopy LG leaving group MeCN methylcyanide (acetonitrile) min minute(s) MS mass spectroscopy MTBE methyltert.-butyl ether NMP N-methyl pyrrolidin-2-one NMR nuclear magneticresonance (spectrum) PBS phosphate buffered saline PE petroleum etherPMBCl para-methoxybenzyl chloride R_(t) retention time RT roomtemperature SGC silica gel chromatography SiO₂ silica gel (forchromatography) TFA trifluoroacetic acid THF tetrahydrofuran TMtransition metal TMS tetramethylsilane Ts para-tolylsulfonyl UVultraviolet (spectrum)

Synthetic Methods

Variables in the formulae of the schemes represent moieties as definedabove unless other meanings are given. The variable R as used hereinrepresents one or two substituents especially such as defined byCR11R12R30 and R31 of formula I. Detailed descriptions of the TypicalProcedures to which reference is made in this section can be found inthe Examples section.

Compounds of the invention having the formula I may be prepared bycombining known synthetic procedures. In a first method3-hydroxy-pyrrolidin-2-one (A) (commercially available as racemicmixture and in both enantiomeric forms) is coupled with indanones B(typically Hal is Br or I) to provide intermediates C. An example forsuitable coupling conditions (CuI, N,N′-dimethyl-ethane-1,2-diamine,cesium carbonate) can be found in the Typical Procedure 1. Conversion ofthe hydroxy group in C to a suitable leaving group (LG is for exampleBr, I, OTs or OPPh₃ ⁺) can be accomplished with various well knownreagents (e.g. PPh₃/I₂, PPh₃/CBr₄, PPh₃/DIAD or TsCl/NEt₃) providing theintermediates D, which may be isolated or may be reacted withoutisolation with hydroxy-aryl building blocks of type E using anappropriate base (e.g. Na₂CO₃, K₂CO₃, Cs₂CO₃ or NaH). For example theconditions in the Typical Procedure 3 may be applied to coupleintermediates C and E to provide compounds I.

A second method of synthesizing compounds I starts with apyrrolidin-2-one substituted with a leaving group (LG) in 3-position(structures F), which may be prepared by reacting A with the reagentsmentioned above. Other procedures for making structures F are known(e.g. base-promoted cyclization of 2,4-dibromo-butyramide).Intermediates F may be isolated or generated in situ to react withhydroxy-aryls E (typically in the presence of a base as described above)to provide intermediates G. As a final step, copper-catalyzed couplingwith aryl halides B provides the desired compounds I (Scheme 1).

Aryl halides B may be prepared by Friedel-Crafts-cyclization of carbonylchlorides derived from 3-(4-halo-phenyl)-propionic acids (substituted byR), which may eventually be further substituted at the positions ofR^(1a), R^(1b) and R^(1c). Other suitable methods to synthesize halidesB include acid (e.g. sulfuric acid) catalyzed cyclizations of saidsubstituted propionic acids.

Another method of synthesizing compounds I uses aryl bromides ofstructure H as starting points. Structures H may be obtained by themethods described above. For example an aryl halide B (R^(1a)═Br) may becoupled to a pyrrolidinone of type G. Further elaboration of structuresH may be done by transition metal catalyzed reactions, which replace thebromo atom by other substituents like other halide, cyano or alkylgroups. Illustrative examples for such reactions can be found in Scheme2.

Certain compounds I (Y═N; Z═O, S, NR6) may be prepared by coupling arylhalides B with hydroxy-pyridines E (Y═N; Z═O, S, NR6). Saidhydroxy-pyridines E may be prepared by displacement of a halide (F, Cl,Br or I) in the 2-position of 5-bromo-2-halo-pyridines, which aresubstituted with R^(2a), R^(2b) and R^(2c), using nucleophiles of thetype HZ—R³—R⁴ (Z═O, S, NR6) followed by conversion of the5-bromo-substituent to a hydroxy group (e.g. by oxidation of a boronategroup introduced by palladium catalyzed coupling withbis-pinacolato-diboron). See Typical Procedure 6 for exemplaryconditions for the nucleophilic displacement reaction, TypicalProcedures 5 and 5a for examples of boronate-oxidation conditions,Typical Procedure 4 for an example of conditions to install a boronategroup and Scheme 3 for illustration of the overall method.

A benzyl group (R³—R⁴═CH₂-Ph) in compounds I (Y═N, Z═O, S) may becleaved for example by hydrogenolysis to provide intermediates J, whichmay be alkylated by LG-R^(3′)—R^(4′), R^(3′) and R^(4′) being definedlike R³ and R⁴ respectively, to yield compounds I (Y═N; Z═O, S).

For example, the structure J may be a 2-hydroxy-pyridine (Z═O), whichmay be alkylated under Mitsunobu-conditions (PPh₃/DIAD; see for exampleTypical Procedure 3) starting with alcohols HO—R^(3′)—R^(4′).Triphenylphosphine may be introduced into the reaction as polymer. DIADmay be replaced by other azodicarboxylates (e.g. DEAD).

Certain other compounds of the invention may be prepared by reaction ofhydroxy-pyrrolidinones C with 6-bromo-3-pyridinols underMitsunobu-conditions and subsequent transition metal catalyzedreplacement of the Br-atom by Z—R³—R⁴.

Variation of the order of the steps in the synthetic sequence providesfurther methods to prepare compounds I. For example intermediates F maybe reacted with 6-bromo-pyridin-3-ols and subsequently thebromo-substituent may be exchanged for Z—R³—R⁴ to provide intermediatesG (Y═N). In a last step, coupling with aryl halides B again providescompounds I (Y═N) as illustrated in Scheme 4.

In another method to prepare compounds I the bicyclic alcohols K(obtained for example by reduction of ketones B) are used as substratesin the CuI-catalyzed coupling reaction with pyrrolidinones G. Theresulting intermediates L are oxidized (e.g. by MnO₂ or Dess-Martinperiodinane) to provide the desired compounds I as illustrated in Scheme5.

Other compounds of formula I (R30=COOH) can be obtained by cleaving anester functionality (R30=COO(C₁-C₆)-alkyl) in the group R (see TypicalProcedure 7 for exemplary conditions). Still other compounds I(R30=CONR14R15) are provided by the reaction of said acids with aminesof the structure HNR14R15 using for example EDCI as coupling reagent(see Typical Procedure 8 for exemplary conditions).

Analytical Methods

Examples were characterized by standard analytical methods. Thisincludes at least two methods (e.g. selected from HPLC, MS, ¹H-NMR). Inparticular, MS and HPLC data were obtained by combined analyticalHPLC/MS (LCMS). For example the following LCMS methods were used.

Method A

Column: Waters UPLC BEH C18 2.1*50 mm, 1.7 μm; mobile phase: (H₂O+0.05%FA): (MeCN+0.035% FA) 98:2 (0 min) to 5:95 (2 min) to 5:95 (2.6 min) to95:5 (2.7 min) to 95:5 (3 min); flow rate: 0.9 mL/min; temperature: 55°C.; ionization method: ES⁺; UV wavelength: 220 nm.

Method B

Column: Waters UPLC BEH C18 2.1*50 mm, 1.7 μm; mobile phase: (H₂O+0.1%FA): (MeCN+0.08% FA) 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min) to95:5 (1.8 min) to 95:5 (2 min); flow rate: 0.9 mL/min; temperature: 55°C.; ionization method: ES⁺; UV wavelength: 220 nm.

Method C

Column: Waters UPLC BEH C18 2.1*50 mm, 1.7 μm; mobile phase: (H₂O+0.05%FA): (MeCN+0.035% FA) 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min)to 95:5 (1.9 min) to 95:5 (2 min); flow rate: 0.9 mL/min; temperature:55° C.; ionization method: ES⁺; UV wavelength: 220 nm.

Method D

Column: Waters UPLC BEH C18 2.1*50 mm, 1.7 μm; mobile phase: (H₂O+0.05%FA): (MeCN+0.035% FA) 95:5 (0 min) to 5:95 (1.1 min) to 5:95 (1.7 min)to 95:5 (1.8 min) to 95:5 (2 min); flow rate: 0.9 mL/min; temperature:55° C.; ionization method: ES⁺; UV wavelength: 220 nm.

Method E

Column: Phenomenex Luna C18(2) 100 Å 2*10 mm, 3 μm; mobile phase:(H₂O+0.05% TFA): MeCN 95:5 (0 min) to 5:95 (1.20 min) to 3:97 (1.40 min)to 96:4 (1.45 min); flow rate: 1.1 mL/min; temperature: 30° C.;ionization method: ES⁺; UV wavelength: 220 nm.

In general, HPLC data is represented by the retention time (R_(t); inmin); MS data is given as the observed mass number (m/z) of the ion[M+H]⁺ (if present) and ¹H-NMR data is reported by lists of chemicalshifts δ (in ppm vs. TMS) of the observed signals (the number ofhydrogen atoms was determined using the area under the respectivesignal; signal multiplicity is characterized as follows: s=singlet,d=doublet, dd=doublet of doublets, t=triplet, dt=doublet of triplets,q=quartet, m=multiplet, br=broad; coupling constants J are given inHertz (Hz)). Deuterated solvents were used for NMR spectroscopy.

EXAMPLES

The following examples are particular embodiments of the invention. Theypartially illustrate the scope of the invention without limiting it.

Abbreviations and chemical symbols have their usual and customarymeanings unless otherwise indicated.

The examples were prepared, isolated and analyzed by the procedures andmethods given. Alternatively they may be prepared by the generalsynthetic methods detailed above. Further variations of the syntheticprocedures may be proposed by a person skilled in the art.

When example compounds containing a basic group were purified bypreparative HPLC on reversed phase column material and, as customary,the eluent was a gradient mixture of water and acetonitrile containingtrifluoroacetic acid (TFA), they were obtained in part in the form oftheir addition salt with TFA, depending on the details of the workupsuch as evaporation or lyophilization conditions. In the names of theexample compounds and their structural formulae any such TFA present isnot specified.

Preparation of Examples 1 Example 1-01 Typical Procedure 1

To a solution of 6-bromo-3-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-one(62 mg) and (R)-3-((6-(4-fluorophenoxy)pyridin-3-yl)oxy)pyrrolidin-2-one(70 mg) in 1,4-dioxane (1 mL) was added N,N′-dimethyl-ethane-1,2-diamine(0.5 mL) and cesium carbonate (130 mg). The mixture was purged for 5minutes with a flow of argon and CuI (30 mg) was added. The mixture washeated at 80° C. for 30 minutes. After cooling to RT insoluble materialwas removed by filtration and the filtrate concentrated. The residue waspurified by preparative HPLC to provide example 1-01.

Following essentially the Typical Procedure 1, the Examples 1 in Table 1were prepared using the respective aryl bromides and 3-substitutedpyrrolidinones.

TABLE 1 LCMS R_(t) ESI⁺ m/z Example Structure Method [min] [amu] 1-01

A 1.70 463.2 1-02

B 1.38 466.2 1-03

D 1.20 490.3 1-04

E 1.03 469.1 1-05

A 1.70 441.3 1-06

A 1.74 451.3 1-07

A 1.73 527.3 1-08

A 1.60 423.3 1-09

A 1.80 469.3 1-10

A 1.75 437.3 1-11

A 1.72 455.2 1-12

A 1.76 451.2 1-13

A 1.61 437.2 1-14

A 1.74 451.2 1-15

A 1.74 451.2 1-16

A 1.65 468.2 1-17

A 1.65 427.1 1-18

A 1.57 409.1

Example 1-07 was obtained as product of partial hydrolysis from thereaction of(6-bromo-4-fluoro-2-methoxycarbonylmethyl-1-oxo-indan-2-yl)-acetic acidmethyl ester and(R)-3-[6-(2-cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-oneaccording to Typical Procedure 1.

Preparation of 3-Substituted Pyrrolidin-2-ones3-[4-(3-Methyl-butoxy)-phenoxy]-pyrrolidin-2-one (Typical Procedure 2)

A mixture of NaH (1.07 g) and THF (30 mL) was added2,4-dibromo-butyramide (3.0 g) at 0° C. After 3 hours,4-(3-methyl-butoxy)-phenol (3.3 g) was added and the mixture heated to65° C. for 4 hours. After standing at room temperature for 12 hours,water was added and the mixture was extracted with MTBE. The organicphase was washed twice (2 N NaOH), dried (Na₂SO₄) and concentrated toprovide the title compound. MS ESI⁺: m/z=264 [M+H]⁺.

4-(3-Methyl-butoxy)-phenol

A mixture of benzene-1,4-diol (20.0 g), DMF (100 mL), cesium carbonate(59.2 g) and 1-bromo-3-methyl-butane (13.7 g) was heated to 60° C. for12 hours. After the mixture reached room temperature, it was distributedbetween water and EA. The organic phase was washed twice (water), dried(Na₂SO₄) and concentrated. The residue was purified by chromatography(SiO₂; EA/heptane 1:2) to provide the subtitle compound. MS ESI⁺:m/z=181 [M+H]⁺.

(R)-3-[6-(4-Fluoro-phenoxy)-pyridin-3-yloxy]-pyrrolidin-2-one (TypicalProcedure 3)

A mixture of THF (200 mL) and DCM (100 mL) under argon was addedtriphenylphosphine (polymer, 1.8 mmol/g, 20 g). Diisopropylazodicarboxylate (8.87 g) was added. After 5 minutes(S)-3-hydroxy-pyrrolidin-2-one (3.1 g) and6-(4-fluoro-phenoxy)-pyridin-3-ol (6.0 g) were added. After 30 minutesthe mixture was filtered and the filtrate concentrated. The residue waspurified by chromatography (SiO₂; DCM/MeOH 15:1) to provide the titlecompound. MS ESI⁺: m/z=289 [M+H]⁺.

6-(4-Fluoro-phenoxy)-pyridin-3-ol

A mixture of 6-bromo-pyridin-3-ol (8.0 g), 4-fluorophenol (15.5 g) andcesium carbonate (30 g) was heated to 170° C. for 6 hours. After themixture reached room temperature, it was distributed between water andMTBE. The organic phase was dried (Na₂SO₄) and concentrated. The residuewas purified by chromatography (SiO₂; EA/heptane 1:1.5) to provide thesubtitle compound. MS ESI⁺: m/z=206 [M+H]⁺.

(R)-3-[4-(4-Fluoro-phenoxy)-phenoxy]-pyrrolidin-2-one

Typical Procedure 3 was followed. Reaction of(S)-3-hydroxy-pyrrolidin-2-one with 4-(4-fluoro-phenoxy)-phenol providedthe title compound. MS ESI⁺: m/z=288 [M+H]⁺.

(R)-3-[6-(2-Cyclopropyl-methoxy)-pyridin-3-yloxy]-pyrrolidin-2-one

A mixture of (S)-3-hydroxy-pyrrolidin-2-one (3.00 g),6-(2-cyclopropyl-methoxy)-pyridin-3-01 (4.90 g), triphenylphosphine(polymer, 8.56 g), DCM (30 mL) and THF (50 mL) was added DIAD (6.60 g)keeping the reaction temperature below 30° C. After 12 hours the mixturewas filtered and the filtrate was evaporated. The residue was purifiedby SGC (eluent: EA/MeOH 9:1) to provide the title compound. MS ESI⁺:m/z=249 [M+H]⁺.

6-Cyclopropylmethoxy-pyridin-3-ol ((Typical Procedure 4)

A mixture of 5-bromo-2-cyclopropylmethoxy-pyridine (8.00 g),bis(pinacolato)diboron (8.91 g) and 1,4-dioxane (53 mL) was purged withargon. Potassium acetate (3.44 g) and Pd(dppf)Cl₂ (2.57 g) were addedand the mixture heated to 100° C. for 1 hour by microwave irradiation.The mixture was filtered and the filtrate diluted with EA, washed withwater, dried (Na₂SO₄) and concentrated. The residue was purified by SGC(eluent: EA/heptane 1:6) to provide the crude boronate. MS ESI⁺: m/z=276[M+H]⁺.

Typical Procedure 5

The boronate from above was dissolved in THF (60 mL). Aqueous NaOH (5 M)was added at 0° C. Hydrogen peroxide (30% in water, 30 mL) was addedslowly. The mixture was allowed to warm to RT and stirred for 4 hours.The mixture was extracted with MTBE. The aqueous phase was adjusted topH 3-4 by addition of diluted HCl and extracted with EA. The organicphase was dried (Na₂SO₄) and concentrated to provide the subtitlecompound. MS ESI⁺: m/z=166 [M+H]⁺.

5-Bromo-2-cyclopropylmethoxy-pyridine (Typical Procedure 6)

To a mixture of 2-cyclopropyl-methanol (6.15 g) and DMF (12 mL) wasadded NaH (60% in mineral oil, 1.5 g) at 0° C. After stirring for 4hours at RT the mixture was diluted with DMF (5 mL) and5-bromo-2-fluoro-pyridine (6.00 g) was slowly added keeping the reactiontemperature below 30° C. After 30 minutes at RT the mixture was heatedto 130° C. for 1 hour by microwave irradiation. After cooling to RT themixture was diluted with EA and washed with water (3 times). The organicphase was dried (Na₂SO₄) and concentrated. The residue was purified bySGC to provide the subtitle compound. MS ESI⁺: m/z=228 [M+H]⁺.

(R)-3-[6-(2-Cyclopropoxy)-pyridin-3-yloxy]-pyrrolidin-2-one

Typical Procedure 3 was followed. Reaction of6-cyclopropoxy-pyridin-3-ol and (S)-3-hydroxy-pyrrolidin-2-one providedthe title compound. MS ESI⁺: m/z=235 [M+H]⁺.

6-Cyclopropoxy-pyridin-3-ol

A mixture of 5-bromo-2-cyclopropoxypyridine (Milestone Pharmtech, 500mg) and THF (10 mL) was cooled (−78° C.) and n-BuLi (2.5 M in toluene,1.49 mL) was added dropwise within 10 minutes. After 20 minutestrimethyl borate (429 μL) was added. After 2 hours peracetic acid (32%in AcOH, 786 μL) was added dropwise. After 10 minutes the reactiontemperature was changed to 0° C. After 1 hour the mixture was pouredinto aqueous NaHSO₃-solution (5%, 5 mL). The mixture was extracted withEA. The organic phase was dried (Na₂SO₄), filtered and concentrated. Theresidue was purified by chromatography (silica gel, heptane toEA/heptane 2:3) to provide the subtitle compound. MS ESI⁺: m/z=152[M+H]⁺.

Preparation of Aryl Bromides6-Bromo-3-(2-hydroxyethyl)-2,3-dihydroinden-1-one

To a solution of 6-bromo-3-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-ol(3.13 g) in DCM (150 mL) was added MnO₂ (5.3 g). The mixture was stirredat RT for 50 hours. The solid was removed by filtration. The filtratewas evaporated and the residue was purified by SGC (DCM/MeOH, 99:1) toprovide the title compound. MS ESI⁺: m/z=255 [M+H]⁺.

6-Bromo-3-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-ol

To a solution of methyl2-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate (4.5 g) in THF (250mL) was added LiAlH₄ (725 mg) at 0° C. and the mixture was allowed towarm to RT with stirring for 2 hours. The mixture was quenched byaddition of water (20 mL) at 0° C., and then NaOH (15%, 9 mL) was added,followed by water (20 mL). The mixture was extracted with EA (50 mL×3).The organic phase was washed with brine (10 mL) and then dried overNa₂SO₄. After filtration and evaporation of the solvent, the residue waspurified by SGC (DCM/MeOH, 99:1) to provide the subtitle compound. MSESI⁺: m/z=257 [M+H]⁺.

Methyl 2-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate

A solution of 3-(4-bromophenyl)pentanedioic acid (10.0 g) in conc. H₂SO₄(60 mL) was heated at 100° C. with stirring for 3 hours. The mixture wascooled to 0° C. and then MeOH (120 mL) was added. The mixture was heatedat 50° C. with stirring for 1 hour and then cooled to room temperature.The reaction mixture was poured into ice water and then extracted withethyl acetate (200 mL×3). The organic phase was dried over Na₂SO₄ andconcentrated. The residue was purified by silica gel columnchromatography eluting with petroleum ether/ethyl acetate (7:1) toprovide the title compound. MS ESI⁺: m/z=283 [M+H]⁺. Separation ofenantiomers was accomplished by chiral HPLC (column: AY-H 250*4.6 mm, 5μm; column temperature: 39.1° C.; eluent: CO₂, co-solvent: EtOH/MeCN=1:1(0.1% DEA); co-solvent: 20%) to provide((S*)-5-bromo-3-oxo-indan-1-yl)-acetic acid methyl ester (faster elatingisomer; preliminary assigned to S-configuration) and((R*)-5-bromo-3-oxo-indan-1-yl)-acetic acid methyl ester (slower elutingisomer; preliminary assigned to R-configuration).

3-(4-Bromophenyl)pentanedioic acid

To a solution of 4-bromobenzaldehyde (25.0 g) in ethyl 3-oxobutanoate(35.1 g) was added piperidine (2.3 g). The mixture was stirred at roomtemperature for 16 hours and the precipitate was washed with ethanol (50mL) to give 38.2 g of a solid. The solid (30.2 g) was added in portionsinto NaOH (50%, 500 g) with stirring. The resulting yellow slurry washeated to reflux with stirring for 3 hours. After cooling to RT, themixture was acidified with conc. HCl to give a white precipitate. Thesolid was collected by filtration, washed with water, and dried undervacuum to provide the subtitle compound as a white solid. MS ESI⁺:m/z=309 [M+Na]⁺.

Methyl 2-(6-bromo-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate

To a solution of 6-bromo-2,3-dihydroinden-1-one (3.0 g) in THF (80 mL)was added LDA (8.5 mL, 2 M solution) dropwise at −78° C. and the mixturewas allowed to warm to 0° C. with stirring for 20 minutes. The mixturewas cooled to −78° C. and methyl 2-bromoacetate (4.35 g) was added. Themixture was allowed to warm to RT with stirring for 3 hours. The mixturewas poured into water and then extracted with EA (100 mL×3). The organicphase was washed with brine and then dried over Na₂SO₄. The solvent wasremoved by evaporation under reduced pressure and the residue waspurified by preparative HPLC to provide the title compound. MS ESI⁺:m/z=283 [M+H]⁺.

Methyl 2-(6-bromo-4-fluoro-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate

To a mixture of diisopropylamine (1.4 mL) and THF (25 mL) was addedn-BuLi (3.4 mL, 2.6 M in toluene) at −78° C. After 30 minutes a solutionof 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (2.0 g) in THF (10 mL)was added dropwise. After 30 minutes methyl 2-bromoacetate (1.34 g) wasadded dropwise. The mixture was allowed to warm to RT with stirring for2 hours. The mixture was poured into an ammonium chloride solution (10%,aqueous) and then extracted with EA (100 mL×3). The organic phase waswashed with brine and then dried over Na₂SO₄. The solvent was removed byevaporation under reduced pressure and the residue was purified by SGC(heptane to EA/heptane=4:1) to provide the title compound. MS ESI⁺:m/z=301 [M+H]⁺. As a second product(6-bromo-4-fluoro-2-methoxycarbonylmethyl-1-oxo-indan-2-yl)-acetic acidmethyl ester was isolated. MS ESI⁺: m/z=373 [M+H]⁺.

6-Bromo-4-fluoro-2-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-one

To a solution of 6-bromo-4-fluoro-2-(2-hydroxy-ethyl)-indan-1-ol (100mg) in 1,4-dioxane (5 mL) was added activated MnO₂ (250 mg). The mixturewas stirred at 90° C. for 5 hours. The solid was removed by filtrationand the filtrate was concentrated. The residue was purified bypreparative HPLC to provide the title compound. MS ESI⁺: m/z=273 [M+H]⁺.

6-Bromo-4-fluoro-2-(2-hydroxy-ethyl)-indan-1-ol

To a mixture of methyl2-(6-bromo-4-fluoro-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate (0.30 g) andTHF (5 mL) at −20° C. was added LiAlH₄ (1 mL, 1 M in THF). The mixturewas allowed to warm to RT with stirring for 1 hour. The volatiles wereremoved and the residue was partitioned between EA and water. Theorganic phase was washed with brine and dried over Na₂SO₄. The solventwas removed by evaporation under reduced pressure to provide the titlecompound. MS ESI⁺: m/z=275 [M+H]⁺.

Methyl 2-(5-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-inden-1-yl)acetate

To methanol (45 mL) was added SOCl₂ (2.49 g) at 0° C., followed by theaddition of a solution of2-(5-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid (1.5 g)in MeOH (5 mL). The mixture was allowed to warm to RT with stirring for4 hours. The solvent was removed by evaporation under reduced pressure.The residue was purified by SGC (PE/EA=20:1) to provide the titlecompound. MS ESI⁺: m/z=303 [M+H]⁺.

2-(5-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic acid

To a solution of 3-(4-bromo-2-fluorophenyl)pentanedioic acid (5.0 g) inDCM (100 mL) was added SOCl₂ (7.8 g) slowly at RT. The mixture wasstirred at RT for 16 hours. The volatiles were removed under reducedpressure and the residue was dried under high vacuum. To the residue,AlCl₃ (8.7 g) was added, and then heated to 130° C. for 12 hours. Thereaction was cooled to RT and the solid was dissolved in EA. The organicphase was washed with water and brine and then dried over Na₂SO₄. Afterfiltration and evaporation of the solvent, the residue was purified bySGC (DCM/MeOH=99:1) to provide the subtitle compound. MS ESI⁺: m/z=287[M+H]⁺.

3-(4-Bromo-2-fluorophenyl)pentanedioic acid

To a solution of 4-bromo-2-fluorobenzaldehyde (35 g) in ethyl3-oxobutanoate (44.8 g) was added piperidine (2.93 g) at RT and themixture was stirred for 15 hours. The crude was purified by SGC(PE/EA=6:1) to give 39 g of a colorless oil. The oil (12 g) was added toNaOH (20 mL, 50%). The resulting slurry was heated to reflux withstirring for 16 hours. After cooling in an ice bath the mixture wasacidified by the addition of conc. HCl to give a white precipitate. Thesolid was collected by filtration and dried to provide the subtitlecompound. MS ESI⁺: m/z=305 [M+H]⁺.

5-Bromo-7-fluoro-N,N-dimethyl-3-oxo-2,3-dihydro-1H-indene-1-carboxamide

To a solution of5-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (850 mg)in DMF (20 mL) was added DIPEA (1.6 g), EDCI (1.2 g) and HOBt (840 mg).The mixture was stirred for 30 minutes. A solution of dimethyl amine(3.1 mL, 2 M in THF) was added. The mixture was stirred for 20 hours.The reaction mixture was partitioned between water (100 mL) and ethylacetate (50 mL×3). The combined organic phases were washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by SGC(PE/EA=2:1) to provide the title compound. MS ESI⁺: m/z=300 [M+H]⁺.

5-Bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid

To a solution of5-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carbonitrile (470 mg) inMeOH (3 mL) was added conc. HCl (12 mL). The mixture was heated toreflux with stirring for 6 hours. The organic solvent was removed underreduced pressure and the aqueous phase was extracted with EA (20 mL×3).The organic phase was washed with brine and dried over Na₂SO₄.Filtration and evaporation of the solvent provided the subtitlecompound. MS ESI⁺: m/z=273 [M+H]⁺.

5-Bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of 3-(4-bromo-2-fluorophenyl)-3-cyanopropanoic acid (1.0g) in DCM (20 mL) was added SOCl₂ (1.75 g) at RT and the mixture wasstirred for 6 hours. The volatiles were removed under reduced pressure.To the residue, AlCl₃ (2.0 g) was added and then heated to 130° C. for2.5 hours. The mixture was cooled to RT and dissolved in EA (100 mL).The organic phase was washed with water and brine, and then dried overNa₂SO₄. After filtration and evaporation of the solvent, the crude waspurified by SGC (PE/EA=10:1) to provide the subtitle compound. MS ESI⁺:m/z=254 [M+H]⁺.

3-(4-Bromo-2-fluorophenyl)-3-cyanopropanoic acid

To a stirred suspension of K₂CO₃ (17.3 g) in DMF (100 mL),2-chloroacetic acid (10 g) was added. From the resulting suspension, DMF(approx. 10 mL) was distilled off under reduced pressure at approx. 54°C. The suspension was cooled to RT and a solution of2-(4-bromo-2-fluorophenyl)acetonitrile (20.6 g) was added. Powdered KOH(10.8 g) was added in portions at 20-25° C. The reaction mixture wasstirred further for 3 hours at RT. The mixture was poured into ice water(800 mL) and then washed with EA (100 mL). The aqueous layer wasacidified with HCl (2 N) and then extracted with EA (200 mL×3). Theorganic phase was dried over Na₂SO₄ and then purified by SGC(DCM/MeOH=99:1) to provide the subtitle compound. MS ESI⁻: m/z=270[M−H]⁻.

6-Bromo-4-fluoro-3-(hydroxymethyl)-2,3-dihydroinden-1-one

To a solution of6-bromo-4-fluoro-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol (150 mg) inDCM (5 mL) was added activated MnO₂ (250 mg). The mixture was stirred at25° C. for 20 hours. The solid was removed by filtration and thefiltrate was concentrated. The residue was purified by SGC(DCM/MeOH=200:1) to provide the title compound. MS ESI⁺: m/z=259 [M+H]⁺.

6-Bromo-4-fluoro-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol

To a solution of5-bromo-7-fluoro-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid (680 mg)in THF (15 mL) was added borane (7.5 mL, 1 M in THF) at RT. The mixturewas heated to reflux for 30 minutes. After cooling, the mixture wasquenched with water and the solvent was removed under reduced pressure.The aqueous phase was extracted with EA (10 mL×3). The combined organicphases were washed with brine and dried over Na₂SO₄. After filtration,the solvent was removed under reduced pressure and the residue waspurified by SGC (DCM/MeOH=99:1) to provide the subtitle compound. MSESI⁺: m/z=283 [M+Na]⁺.

6-Bromo-3-(hydroxymethyl)-2,3-dihydroinden-1-one

To a solution of 6-bromo-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol(1.3 g) in DCM (20 mL) was added activated MnO₂ (2.3 g). The mixture wasstirred at 25° C. for 15 hours. Additional activated MnO₂ (930 mg) wasadded, and the suspension was stirred at 25° C. for 20 hours. The solidwas removed by filtration and the filtrate was concentrated. The residuewas purified by column chromatography on silica gel eluting withDCM/MeOH=99:1 to provide the title compound. MS ESI⁺: m/z=241 [M+H]⁺.

6-Bromo-3-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ol

To a solution of methyl5-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylate (1.5 g) in THF (40 mL)was added LiAlH₄ (4 mL, 1 M in THF) at 0° C. The mixture was stirred at0° C. for 30 minutes and then quenched by the addition of brine (20 mL).The mixture was extracted with EA (30 mL×3). The organic phase waswashed with brine (10 mL) and dried over Na₂SO₄. After filtration, thesolvent was removed under reduced pressure to provide the subtitlecompound. MS ESI⁺: m/z=265 [M+Na]⁺.

Methyl 5-bromo-3-oxo-2,3-dihydro-1H-indene-1-carboxylate

Thionylchloride (15.6 g) was added to MeOH (100 mL) at 0° C., followedby the addition of a solution of5-bromo-3-oxo-2,3-dihydro-1H-indene-1-carbonitrile (2.06 g) in MeOH (50mL). The mixture was allowed to warm to RT and then heated to refluxwith stirring for 4 hours. After cooling, the solvent was removed invacuo. The residue was purified by SGC (PE/EA=8:1) to provide thesubtitle compound. MS ESI⁺: m/z=269 [M+H]⁺.

5-Bromo-3-oxo-2,3-dihydro-1H-indene-1-carbonitrile

To a solution of 3-(4-bromophenyl)-3-cyanopropanoic acid (1 g) in DCM(15 mL) was added SOCl₂ (2.3 g) at RT and stirred for 6 hours. Thesolvent was removed under reduced pressure. To the residue, AlCl₃ (2.6g) was added and the mixture was heated to 130° C. for 1.5 hours. Aftercooling, the solid was dissolved in EA (100 mL). The organic phase waswashed with water (100 mL) and brine (20 mL) and then dried over Na₂SO₄.After filtration and evaporation of the solvent, the residue waspurified by SGC (PE/EA=7:1) to provide the subtitle compound. MS ESI⁺:m/z=236 [M+H]⁺.

3-(4-Bromophenyl)-3-cyanopropanoic acid

To a stirred suspension of K₂CO₃ (5.03 g) in DMF (20 mL), 2-chloroaceticacid (2.93 g) was added. From the resulting suspension, DMF (approx. 5mL) was distilled off under reduced pressure at approx. 54° C. (for 30min). The suspension was cooled to RT. A solution of2-(4-bromophenyl)acetonitrile (5.5 g) in DMF (20 mL) was added. PowderedKOH (3.14 g) was added in portions at 20-25° C. The suspension wasstirred for 2 hours. The reaction mixture was poured into water (300 mL)and then washed with EA (50 mL×2). The aqueous phase was adjusted to pH2 with 2 N HCl and extracted with EA (100 mL×3). The combined organicphases were washed with brine (30 mL) and dried over Na₂SO₄. Afterfiltration and evaporation of the solvent, the residue was purified bySGC (DCM/MeOH=99:1) to provide the subtitle compound. MS ESI⁻: m/z=252[M−H]⁻.

6-Bromo-1-oxo-indan-2-carboxylic acid methyl ester

To a mixture of 6-bromo-indan-1-one (10.0 g) and dimethylcarbonate (107g) was added NaH (4.17 g, 60% in mineral oil). After heating at 80° C.for 2 hours the mixture was allowed to cool to rt, quenched by additionof ammonium chloride solution and extracted with EA. The organic phasewas washed with brine, dried over Na₂SO₄ and concentrated to provide thetitle compound. MS ESI⁺: m/z=269 [M+H]⁺.

Preparation of Examples 2 Example 2-01 Typical Procedure 7

A mixture of methyl2-(6-((R)-3-((6-(cyclopropylmethoxy)pyridin-3-yl)oxy)-2-oxopyrrolidin-1-yl)-4-fluoro-1-oxo-2,3-dihydro-1H-inden-2-yl)acetate(11 mg) and THF (0.2 mL) was added LiOH (13 μL, 2 M in water) andstirred for 12 hours. The mixture was acidified (0.1 M HCl) andextracted with EA. The organic phase was dried (Na₂SO₄) andconcentrated. The residue was purified by preparative HPLC to provideExample 2-01.

Following essentially this procedure, the Examples 2 in Table 2 wereobtained by saponification of the respective methyl esters.

TABLE 2 LCMS R_(t) ESI⁺ m/z Example Structure Method [min] [amu] 2-01

E 0.95 455   2-02

A 1.61 437.3 2-03

A 1.68 455.3 2-04

A 1.60 437.2 2-05

A 1.60 437.1

Preparation of Examples 3 Example 3-01 Typical Procedure 8

To a mixture of2-((R)-5-(3-((6-(cyclopropylmethoxy)pyridin-3-yl)oxy)-2-oxopyrrolidin-1-yl)-3-oxo-2,3-dihydro-1H-inden-1-yl)aceticacid (100 mg), DIPEA (148 mg) and DMF (2 mL) was added EDCI (54 mg) andHOBt (31 mg). After 30 minutes dimethyl amine (340 μL, 1 M in THF) wasadded and the mixture stirred for 12 hours. Evaporation of the reactionmixture gave a residue which was purified by preparative HPLC to provideExample 3-01.

Following essentially this procedure the Examples 3 in Table 3 wereobtained by coupling the appropriate acid (selected from Examples 2)with the respective amine.

TABLE 3 LCMS R_(t) ESI⁺ m/z Example Structure Method [min] [amu] 3-01

A 1.68 464.4 3-02

A 1.61 450.4 3-03

A 1.68 476.4 3-04

A 1.59 436.3 3-05

A 1.61 454.3 3-06

A 1.73 482.3 3-07

A 1.71 524.3 3-08

A 1.63 468.3 3-09

A 1.61 498.4 3-10

A 1.60 454.3 3-11

A 1.72 482.4

Pharmacological Utility

The biological activity of the compounds of the invention may bedemonstrated by known in vitro assays. Examples include in vitrocellular assays for recombinant and non-recombinant GPR119 as describedin the following.

Functional Cellular Assays Measuring GPR119-Mediated cAMP Release

Compounds of the invention, which are agonists of GPR119, werecharacterized by functional assays measuring the cAMP response ofHEK-293 cell lines stably expressing recombinant GPR119 from man, mouseor rat, or by using a hamster cell line HIT-T15 expressing GPR119endogenously. The cAMP content was determined using a kit based onhomogenous time-resolved fluorescence (HTRF) from Cisbio Corp. (cat. no.62AM4PEC). For preparation, cells were split into T175 culture flasksand grown to near confluency in medium (DMEM/10% FCS for HEK-293 cells,and F-12K medium/10% horse serum/2.5% FCS for HIT-T15 cells,respectively). Medium was then removed and cells washed with PBS lackingcalcium and magnesium ions, followed by proteinase treatment withaccutase (Sigma-Aldrich, cat. no. A6964). Detached cells were washed andresuspended in assay buffer (1×HBSS; 20 mM HEPES, 0.1% BSA, 2 mM IBMX)and cellular density determined. They were then diluted to 400000cells/mL and 25 μL-aliquots dispensed to the wells of 96-well plates.For measurement, 25 μL of test compound in assay buffer was added andincubated for 30 minutes at room temperature. After addition of HTRFreagents diluted in lysis buffer, the plates were incubated for 1 hour,followed by measuring the fluorescence ratio at 665 vs. 620 nm. Potencyof the agonists was quantified by determining the concentrations thatcaused 50% of the maximal response/activation (EC₅₀). See Table 4 forexemplary data obtained using the cell line expressing human GPR119.

Compounds of the invention show EC₅₀ values typically in the range ofabout 0.001 to 100 μM, preferably from about 0.001 to 10 μM, morepreferably from about 0.001 to 1 μM and most preferably from about 0.001to 0.3 μM.

TABLE 4 EC₅₀ Example [μM] 1-01 0.311 1-02 0.262 1-03 0.111 1-04 0.0141-05 0.233 1-06 0.019 1-07 0.332 1-08 0.079 1-09 0.012 1-10 0.041 1-110.038 1-12 0.029 1-13 0.098 1-14 0.019 1-15 0.016 1-16 0.117 1-17 0.0721-18 0.198 2-01 0.360 2-02 0.135 2-03 0.218 2-04 0.505 2-05 1.990 3-010.082 3-02 0.188 3-03 0.339 3-04 0.320 3-05 0.078 3-06 0.046 3-07 0.0833-08 0.066 3-09 0.289 3-10 0.073 3-11 0.059 empty empty empty empty

Based on the demonstrated ability of the compounds of the invention toactivate GPR119 it is predicted that said compounds are useful fortreatment of diseases and/or prevention of conditions which aremodulated by GPR119.

Especially, the compounds of the invention may be useful to treatGPR119-related diseases and/or prevent GPR119-mediated conditions inhumans.

The compounds of the invention are especially suitable for the treatmentand/or prevention of:

-   -   1a) Disorders of fatty acid metabolism and glucose utilization        disorders    -   1b) Disorders in which insulin resistance is involved    -   2) Diabetes mellitus, especially type 2 diabetes mellitus,        including the prevention of the sequelae associated therewith.        Particular aspects in this context are:        -   a) Improvement of hyperglycemia        -   b) Improvement of insulin resistance        -   c) Improvement of glucose tolerance        -   d) Protection of pancreatic beta cells        -   e) Improvement of beta cell function        -   f) Prevention of micro- and macrovascular disorders, such as            -   a. Retinopathy            -   b. Atherosclerosis            -   c. Nephropathy and microalbuminuria            -   d. Neuropathy        -   g) Chronic low grade inflammation    -   3) Various other conditions which may be associated with the        metabolic syndrome or the syndrome X, such as        -   a) Increased abdominal girth        -   b) Obesity        -   c) Liver disorders            -   a. Fatty liver            -   b. Steatosis            -   c. Steatohepatitis            -   d. Cirrhosis        -   d) Dyslipidemia (e.g. hypertriglyceridemia,            hypercholesterolemia, hyperlipoproteinemia and/or low HDL)        -   e) Insulin resistance        -   f) Hypercoagulability        -   g) Hyperuricemia        -   h) Thromboses, hypercoagulable and prothrombotic states            (arterial and venous)        -   i) High blood pressure        -   j) Endothelial dysfunction        -   k) Heart failure, for example (but not limited to) following            myocardial infarction, hypertensive heart disease or            cardiomyopathy    -   4) Cardiovascular diseases, for example (but not limited to)        myocardial infarction and stroke    -   5) Bone-related diseases and disorders characterized by reduced        bone mass, such as:        -   a) Osteoporosis        -   b) Rheumatoid arthritis        -   c) Osteoarthritis.

1: A compound of the formula I

in which R30 is (CR11′R12′)-R32, NR17R18 or OR17; R31 is H or(CR11′R12′)-R32; n is 0, 1 or 2; m is 0, 1, 2 or 3; R11, R12 areindependently of each other H or (C₁-C₆)-alkyl; or R11 and R12 formtogether the group ═O; R11′, R12′ are independently of each other H or(C₁-C₆)-alkyl; R32 is (C₁-C₆)-alkyl, COOR13, CONR14R15, SO₂R16 or OH;R13 is H or (C₁-C₆)-alkyl; R14, R15 are independently of each other H,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted with OR17, or(C₃-C₆)-cycloalkyl; or R14 and R15 form together with the N-atom onwhich they are attached, a 4-, 5- or 6-membered heterocycle, optionallycontaining an additional heteroatom selected from the list O, S andNR18; wherein the 4-, 5- or 6-membered heterocycle may be optionallysubstituted with 1 to 3 groups selected from the list (C₁-C₄)-alkyl andOR19; R16 is (C₁-C₆)-alkyl; R17 is H or (C₁-C₆)-alkyl; R18 is H or(C₁-C₆)-alkyl; R19 is H or (C₁-C₆)-alkyl; R1a, R1b, R1c areindependently of each other H, F, Cl, Br, (C₁-C₆)-alkyl or CN; R2a, R2b,R2c are independently of each other H, F, Cl, Br, (C₁-C₆)-alkyl or CN; Yis N or CH; Z is a bond, O, CR5R5′, NR6, C═O, S, SO or SO₂; R5, R5′, R6are independently of each other H or (C₁-C₄)-alkyl; R3 is a bond or(CR7R7′)_(p); p is 0, 1, 2, 3 or 4; R7, R7′ are independently of eachother H or (C₁-C₆)-alkyl; R4 is (C₁-C₆)-alkyl, OR8, (C₃-C₈)-cycloalkyl,(C₅-C₈)-bicycloalkyl, 4-, 5- or 6-membered heterocycle, phenyl or 5- or6-membered heteroaryl ring; wherein the groups (C₃-C₈)-cycloalkyl,(C₅-C₈)-bicycloalkyl, 4-, 5- or 6-membered heterocycle, phenyl, 5- or6-membered heteroaryl ring may be optionally substituted with 1 to 3groups selected from (C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl, hydroxy,hydroxy-(C₁-C₄)-alkyl, (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl, oxo, F or Cl; R8is H, (C₁-C₆)-alkyl, hydroxy-(C₁-C₄)-alkyl or(C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl; wherein at each occurrence the hydrogenatoms of alkyl groups may be partially or fully replaced by fluorineatoms; in any of its stereoisomeric forms, or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof. 2: A compound of the formula I as claimed in claim 1, whereinthe 3-position of the pyrrolidinone ring has (R)-configuration. 3: Acompound of the formula I as claimed in claim 1, wherein Y is N. 4: Acompound of the formula I as claimed in claim 1, wherein Z is O. 5: Acompound of the formula I as claimed in claim 1, wherein R3 is CH₂. 6: Acompound of the formula I as claimed in claim 1, wherein R4 is(C₃-C₈)-cycloalkyl. 7: A compound of the formula I as claimed in claim1, which is a compound of the formula Ia

in which R30 is (CR11′R12′)-R32 or OR17; n is 0, 1 or 2; R11′, R12′ areindependently of each other H or (C₁-C₆)-alkyl; R32 is COOR13,CONR14R15, SO₂R16 or OH; R13 is H or (C₁-C₆)-alkyl; R14, R15 areindependently of each other H, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substitutedwith OR17, or (C₃-C₆)-cycloalkyl; or R14 and R15 form together with theN-atom on which they are attached, a 4-, 5- or 6-membered heterocycle,optionally containing an additional heteroatom selected from the list O,S and NR18; wherein the 4-, 5- or 6-membered heterocycle may beoptionally substituted with 1 to 3 groups selected from the list(C₁-C₄)-alkyl and OR19; R16 is (C₁-C₆)-alkyl; R17 is H or (C₁-C₆)-alkyl;R18 is H or (C₁-C₆)-alkyl; R19 is H or (C₁-C₆)-alkyl; R1a, R1c areindependently of each other H, F, Cl, Br, (C₁-C₆)-alkyl or CN; R2a is H,F, Cl, Br, (C₁-C₆)-alkyl or CN; R3 is a bond or (CR7R7′)_(p); p is 0, 1,2, 3 or 4; R7, R7′ are independently of each other H or (C₁-C₆)-alkyl;R4 is (C₁-C₆)-alkyl, OR8, (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-,5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroarylring; wherein the groups (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-,5- or 6-membered heterocycle, phenyl, 5- or 6-membered heteroaryl ringmay be optionally substituted with 1 to 3 groups selected from(C₁-C₄)-alkyl, (C₁-C₄)-alkanoyl, hydroxy, hydroxy-(C₁-C₄)-alkyl,(C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl, oxo, F or Cl; R8 is H, (C₁-C₆)-alkyl,hydroxy-(C₁-C₄)-alkyl or (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl; wherein at eachoccurrence the hydrogen atoms of alkyl groups may be partially or fullyreplaced by fluorine atoms; in any of its stereoisomeric forms, or amixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof. 8: A compound of the formula I as claimed inclaim 7, wherein R30 is (CR11′R12′)-R32 or OR17; n is 0, 1 or 2; R11′,R12′ are independently of each other H or (C₁-C₆)-alkyl R32 is(C₁-C₆)-alkyl, COOR13, CONR14R15, SO₂R16 or OH; R13 is H or(C₁-C₆)-alkyl; R14, R15 are independently of each other H,(C₁-C₆)-alkyl, (C₁-C₆)-alkyl substituted with OR17, or(C₃-C₆)-cycloalkyl; or R14 and R15 form together with the N-atom onwhich they are attached, a 4-, 5- or 6-membered heterocycle, optionallycontaining an additional heteroatom selected from the list O, S andNR18; wherein the 4-, 5- or 6-membered heterocycle may be optionallysubstituted with 1 to 3 groups selected from the list (C₁-C₄)-alkyl andOR19; R16 is (C₁-C₆)-alkyl; R17 is H or (C₁-C₆)-alkyl; R18 is H or(C₁-C₆)-alkyl; R19 is H or (C₁-C₆)-alkyl; R1a, R1c are independently ofeach other H, F, Cl, Br, (C₁-C₆)-alkyl or CN; R2a is H, F, Cl, Br,(C₁-C₆)-alkyl or CN; R3 is bond, CH₂ or CH₂—CH₂; R4 is (C₁-C₆)-alkyl,OR8, (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-, 5- or 6-memberedheterocycle, phenyl or 5- or 6-membered heteroaryl ring; wherein thegroups (C₃-C₈)-cycloalkyl, (C₅-C₈)-bicycloalkyl, 4-, 5- or 6-memberedheterocycle, phenyl, 5- or 6-membered heteroaryl ring may be optionallysubstituted with 1 to 3 groups selected from (C₁-C₄)-alkyl,(C₁-C₄)-alkanoyl, hydroxy, hydroxy-(C₁-C₄)-alkyl,(C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl, oxo, F or Cl; R8 is H, (C₁-C₆)-alkyl,hydroxy-(C₁-C₄)-alkyl or (C₁-C₃)-alkyloxy-(C₁-C₄)-alkyl; wherein at eachoccurrence the hydrogen atoms of alkyl groups may be partially or fullyreplaced by fluorine atoms; in any of its stereoisomeric forms, or amixture of stereoisomeric forms in any ratio, or a physiologicallyacceptable salt thereof. 9: A compound of the formula Ia as claimed inclaim 7, wherein R30 is (CR11′R12′)-R32 or OR17; n is 0, 1 or 2; R11′,R12′ are independently of each other H or (C₁-C₆)-alkyl; R32 is COOR13,CONR14R15, SO₂R16 or OH; R13 is H or (C₁-C₆)-alkyl; R14, R15 areindependently of each other H, (C₁-C₆)-alkyl, (C₁-C₆)-alkyl substitutedwith OR17, or (C₃-C₆)-cycloalkyl; or R14 and R15 form together with theN-atom on which they are attached, a 4-, 5- or 6-membered heterocycle,optionally containing an additional heteroatom selected from the list O,S and NR18; wherein the 4-, 5- or 6-membered heterocycle may beoptionally substituted with 1 to 3 groups selected from the list(C₁-C₄)-alkyl and OR19; R16 is (C₁-C₆)-alkyl; R17 is H or (C₁-C₆)-alkyl;R18 is H or (C₁-C₆)-alkyl; R19 is H or (C₁-C₆)-alkyl; R1a, R1c areindependently of each other H, F, Cl, Br, (C₁-C₆)-alkyl or CN; R2a is H,F, Cl, Br, (C₁-C₆)-alkyl or CN; R3 is bond, CH₂ or CH₂—CH₂; R4(C₃-C₈)-cycloalkyl; in any of its stereoisomeric forms, or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof. 10: A compound of the formula Ia as claimed in claim 7, whereinR30 is R32; R32 is CONR14R15, COOR13; R13 is H or (C₁-C₆)-alkyl; R14,R15 are independently of each other H, (C₁-C₆)-alkyl or (C₁-C₆)-alkylsubstituted with OR17; or R14 and R15 form together with the N-atom onwhich they are attached, a 4-, 5- or 6-membered heterocycle, optionallycontaining an additional heteroatom selected from the series O, S andNR18; R17 is H or (C₁-C₆)-alkyl; R18 is H or (C₁-C₆)-alkyl; R1a, R1c areindependently of each other H, F, Cl, Br, (C₁-C₆)-alkyl or CN; R2a is H,F, Cl, Br, (C₁-C₆)-alkyl or CN; R3 is CH₂; R4 (C₃-C₆)-cycloalkyl; in anyof its stereoisomeric forms, or a mixture of stereoisomeric forms in anyratio, or a physiologically acceptable salt thereof. 11: A compound ofthe formula Ia as claimed in claim 7, wherein R30 is R32; R32 isCONR14R15, COOR13; R14, R15 are independently of each other H,(C₁-C₆)-alkyl or (C₁-C₆)-alkyl substituted with OR17; R17 is H or(C₁-C₆)-alkyl; R1a is H or F; R1c is H; R2a is H; R3 is CH₂; R4(C₃-C₆)-cycloalkyl; in any of its stereoisomeric forms, or a mixture ofstereoisomeric forms in any ratio, or a physiologically acceptable saltthereof. 12: A compound selected from the list5-[(3R)-3-[[6-(Cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-N,N-dimethyl-3-oxo-indane-1-carboxamide,2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamide,2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N-methyl-acetamide,2-[6-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-4-fluoro-1-oxo-indan-2-yl]-N,N-dimethyl-acetamide,2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]acetamideand2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamideor a pharmaceutically acceptable salt thereof. 13: The compound2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-3-oxo-indan-1-yl]-N,N-dimethyl-acetamideor a pharmaceutically acceptable salt thereof. 14: The compound2-[5-[(3R)-3-[[6-(cyclopropylmethoxy)-3-pyridyl]oxy]-2-oxo-pyrrolidin-1-yl]-7-fluoro-3-oxo-indan-1-yl]-N,N-dimethyl-acetamideor a pharmaceutically acceptable salt thereof. 15: A pharmaceuticalcomposition comprising at least one compound as claimed in claim 1 or aphysiologically acceptable salt of any of them, for use as apharmaceutical. 16: A pharmaceutical composition as claimed in claim 15,comprising additionally one or more active ingredients selected from thelist: Insulin and insulin derivatives, GLP-1, GLP-1 analogues and GLP-1receptor agonists, polymer bound GLP-1 and GLP-1 analogues, dualGLP-1/GIP agonists, dual GLP-1/glucagon receptor agonists, PYY3-36 oranalogues thereof, pancreatic polypeptide or analogues thereof, glucagonreceptor agonists or antagonists, GIP receptor agonists or antagonists,ghrelin antagonists or inverse agonists, xenin and analogues thereof,DDP-IV inhibitors, SGLT-2 inhibitors, dual SGLT-2/SGLT-1 inhibitors,biguanides, thiazolidinediones, PPAR agonists, PPAR modulators,sulfonylureas, meglitinides, alpha-glucosidase inhibitors, amylin andamylin analogues, GPR119 agonists, GPR40 agonists, GPR120 agonists,GPR142 agonists, TGR5 agonists, AMPK stimulants, AMPK activators,inhibitors of 11-beta-HSD, activators of glucokinase, inhibitors ofDGAT, inhibitors of protein tyrosine phosphatase 1, inhibitors ofglucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase,inhibitors of glycogen phosphorylase, inhibitors of phosphoenol pyruvatecarboxykinase, inhibitors of glycogen synthase kinase, inhibitors ofpyruvate dehydrogenase kinase, CCR-2 antagonists, modulators of glucosetransporter-4, somatostatin receptor 3 agonists, HMG-CoA-reductaseinhibitors, fibrates, nicotinic acid and derivatives thereof, nicotinicacid receptor 1 agonists ACAT inhibitors, cholesterol absorptioninhibitors, bile acid-binding substances, IBAT inhibitors, MTPinhibitors, modulators of PCSK9, LDL receptor up-regulators (liverselective thyroid hormone receptor beta agonists), HDL-raisingcompounds, lipid metabolism modulators, PLA2 inhibitors, ApoA-Ienhancers, cholesterol synthesis inhibitors, omega-3 fatty acids andderivatives thereof, active substances for the treatment of obesity, CB1receptor antagonists, MCH-1 antagonists, MC4 receptor agonists andpartial agonists, NPY5 or NPY2 antagonists, NPY4 agonists, beta-3adrenergic receptor agonists, leptin or leptin mimetics, 5HT2c receptoragonists, lipase inhibitors, angiogenesis inhibitors, H3 antagonists,AgRP inhibitors, triple monoamine uptake inhibitors, MetAP2 inhibitors,antisense oligonucleotides against production of fibroblast growthfactor receptor 4 or prohibitin targeting peptide-1, drugs forinfluencing high blood pressure, chronic heart failure oratherosclerosis, angiotensin II receptor antagonists, dual angiotensinreceptor blockers (ARB), angiotensin converting enzyme (ACE) inhibitors,angiotensin converting enzyme 2 (ACE-2) activators renin inhibitors,prorenin inhibitors, endothelin converting enzyme (ECE) inhibitors,endothelin receptor blockers, endothelin antagonists, diuretics,aldosterone antagonists, aldosterone synthase inhibitors,alpha-blockers, antagonists of the alpha-2 adrenergic receptor,beta-blockers, mixed alpha-/beta-blockers, calcium antagonists/calciumchannel blockers (CBBs), dual mineralocorticoid/CCBs, centrally actingantihypertensives, inhibitors of neutral endopeptidase, aminopeptidase-Ainhibitors, vasopeptide inhibitors, dual vasopeptide inhibitors,neprilysin-ACE inhibitors, neprilysin-ECE inhibitors, dual-actingAngiotensin (AT) receptor-neprilysin inhibitors, dual AT1/endothelin-1(ETA) antagonists, advanced glycation end-product breakers, recombinantrenalase, blood pressure vaccines, anti-RAAS vaccines, AT1- orAT2-vaccines, modulators of genetic polymorphisms with antihypertensiveresponse and thrombocyte aggregation inhibitors. 17: A pharmaceuticalcomposition as claimed in claim 15, comprising additionally metformin.18: A pharmaceutical composition as claimed in claim 15, comprisingadditionally at least one DPP-IV inhibitor. 19: A pharmaceuticalcomposition as claimed in claim 18, wherein the DPP-IV inhibitor isselected from the list alogliptin, linagliptin, saxagliptin,sitagliptin, anagliptin, teneligliptin, trelagliptin, vildagliptin,gemigliptin, omarigliptin, evogliptin and dutogliptin. 20: Apharmaceutical composition as claimed in claim 15, comprisingadditionally at least one SGLT-2 inhibitor. 21: A pharmaceuticalcomposition as claimed in claim 20, wherein the SGLT-2 inhibitor isselected from the list canagliflozin, dapagliflozin, remogliflozin,remogliflozin etabonate, sergliflozin, empagliflozin, ipragliflozin,tofogliflozin, luseogliflozin and ertugliflozin. 22: A pharmaceuticalcomposition as claimed in claim 15, comprising additionally at least oneGPR40 agonist. 23: A pharmaceutical composition as claimed in claim 22,wherein the GPR40 agonist is selected from the list TUG-424, P-1736,P-11187, JTT-851, GW9508, CNX-011-67, AM-1638 and AM-5262. 24: Apharmaceutical composition as claimed in claim 15, comprisingadditionally ezetimibe. 25: A pharmaceutical composition as claimed inclaim 15, comprising additionally at least one HMG-CoA reductaseinhibitor. 26: A pharmaceutical composition as claimed in claim 25,wherein the HMG-CoA reductase inhibitor is selected from the listsimvastatin, atorvastatin, rosuvastatin, pravastatin, fluvastatin,pitavastatin, lovastatin, mevastatin, rivastatin and cerivastatin. 27: Apharmaceutical composition as claimed in claim 15, comprisingadditionally at least one PPAR agonist or PPAR modulator. 28: Apharmaceutical composition as claimed in claim 27, wherein the PPARagonist or PPAR modulator is saroglitazar. 29: A pharmaceuticalcomposition as claimed in claim 27, wherein the PPAR agonist or PPARmodulator is selected from the list pioglitazone, rosiglitazone andlobeglitazone. 30: A pharmaceutical composition as claimed in claim 15,comprising additionally acarbose. 31: A compound of the formula I asclaimed in claim 1 for use as a pharmaceutical. 32: A compound of theformula I as claimed in claim 1 for the prevention and/or treatment ofdiabetes, obesity, dyslipidemia and related disorders. 33: A compound ofthe formula I as claimed in claim 1 for the prevention and/or treatmentof diabetes. 34: A compound of the formula I as claimed in claim 1 forthe prevention and/or treatment of obesity. 35: A compound of theformula I as claimed in claim 1 for the prevention and/or treatment ofdyslipidemia. 36: A compound of the formula I as claimed in claim 1 forprevention and/or treatment of a disease associated with the GPR119. 37:A method for treating diabetes, obesity or dyslipidemia in a patient,the method comprising administering to the patient an effective amountof at least one compound of formula I as claimed in claim
 1. 38: Amethod for treating diabetes, obesity, dyslipidemia or high bloodpressure in a patient, the method comprising administering to thepatient an effective amount of at least one compound of formula I asclaimed in claim 1 and an effective amount of at least one othercompound useful for treating diabetes, obesity, dyslipidemia or highblood pressure. 39: The method as claimed in claim 38 wherein theeffective amount of at least one compound of formula I and theadditional active ingredient are adminstered to the patientsimultaneously. 40: The method as claimed in claim 38 wherein theeffective amount of at least one compound of formula I and theadditional active ingredient are adminstered to the patientsequentially.